EP1912949A1 - Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors - Google Patents

Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors

Info

Publication number
EP1912949A1
EP1912949A1 EP06776307A EP06776307A EP1912949A1 EP 1912949 A1 EP1912949 A1 EP 1912949A1 EP 06776307 A EP06776307 A EP 06776307A EP 06776307 A EP06776307 A EP 06776307A EP 1912949 A1 EP1912949 A1 EP 1912949A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
alkylene
halogen
compound according
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP06776307A
Other languages
German (de)
French (fr)
Other versions
EP1912949B1 (en
Inventor
Oliver Plettenburg
Armin Hofmeister
Dieter Kadereit
Joachim Brendel
Matthias Loehn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi Aventis France
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
Priority to PL06776307T priority Critical patent/PL1912949T3/en
Priority to SI200631175T priority patent/SI1912949T1/en
Priority to EP06776307A priority patent/EP1912949B1/en
Publication of EP1912949A1 publication Critical patent/EP1912949A1/en
Application granted granted Critical
Publication of EP1912949B1 publication Critical patent/EP1912949B1/en
Priority to CY20111101153T priority patent/CY1112085T1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/16—Central respiratory analeptics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel isoquinolone and isoquinoline derivatives as described in the claims, their preparation and their use in the treatment and/or prevention of diseases related to the inhibition of Rho-kinase and/or of Rho-kinase mediated phosphorylation of myosin light chain phosphatase.
  • Rho-kinase 2 Activation of a small GTPase RhoA upon agonist stimulation results in conversion of RhoA from the inactive GDP-bound form to the active GTP-bound form with a subsequent binding to and activation of Rho-kinase.
  • Rho-kinase 1 and Rho-kinase 2 Two isoforms, Rho-kinase 1 and Rho-kinase 2, are known.
  • Rho-kinase 2 is expressed in vascular smooth muscle cells and endothelial cells.
  • Rho-kinase 2 Activation of Rho-kinase 2 by the active GTP-bound RhoA leads to calcium sensitization of smooth muscle cells through phosphorylation-mediated inhibition of the myosin light chain phosphatase activity and thereby up-regulation of the activity of myosin regulatory light chain (Uehata et al., Nature 1997, 389, 990-994).
  • Rho-kinase is involved in vasoconstriction, including the development of myogenic tone and smooth muscle hypercontractility (Gokina et al. J. Appl. Physiol. 2005, 98, 1940-8), bronchial smooth muscle contraction (Yoshii et al. Am. J. Resp. Cell MoI. Biol. 20, 1190-1200), asthma (Setoguchi et al. Br J Pharmacol. 2001 , 132,111-8; Nakahara, et al. Eur J 2000,389,103) and chronic obstructive pulmonary disease (COPD, Maruoka, Nippon Rinsho, 1999 , 57, 1982-7), hypertension, pulmonary hypertension (Fukumoto et al.
  • nephropathy including hypertension-induced, non-hypertension-induced, and diabetic nephropathies
  • PAOD peripheral occlusive arterial disease
  • myocardial infarction Demiryurek et al. Eur J Pharmacol. 2005, 527, 129-40, Hattori et al. Circulation, 2004, 109,2234-9
  • cardiac hypertrophy and failure Yamakawa, et al. Hypertension 2000, 35, 313-318, Liao et al. Am J Physiol Cell Physiol.
  • sexual dysfunction e.g., penile erectile dysfunction (Chitaley et al. Nature Medicine 2001 , 7, 119-122), retinopathy, inflammation, immune diseases, AIDS, osteoporosis, endocrine dysfunctions, e.g. hyperaldosteronism, central nervous system disorders such as neuronal degeneration and spinal cord injury (Hara, et al. JNeurosurg 2000, 93, 94), cerebral ischemia (Uehata, et al. Nature 1997,389,990; Satoh et al. Life Sci. 2001 , 69, 1441-53; Hitomi, et al.
  • a compound having inhibitory effect on Rho-kinase and/or on Rho-kinase mediated phosphorylation of myosin light chain phosphatase is useful for the treatment and/or prevention of cardiovascular and non-cardiovascular diseases involving Rho- kinase as the primary or secondary disease cause, like hypertension, pulmonary hypertension, ocular hypertension, retinopathy, and glaucoma, peripheral circulatory disorder, peripheral occlusive arterial disease (PAOD), coronary heart disease, angina pectoris, heart hypertrophy, heart failure, ischemic diseases, ischemic organ failure (end organ damage), fibroid lung, fibroid liver, liver failure, nephropathy, including hypertension-induced, non-hypertension-induced, and diabetic nephropathies, renal failure, fibroid kidney, renal glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, thrombotic disorders, stroke, cerebral
  • neuropathic pain neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes and complications of diabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy such as osteoporosis, infection of digestive tracts with bacteria, sepsis, cancer development and progression, e.g. cancers of the breast, colon, prostate, ovaries, brain and lung and their metastases.
  • WO 01/64238 describes isoquinoline-5-sulfonamide derivatives optionally substituted by a -(CH 2 )i-6-0-(CH 2 )o-6-. a -(CH 2 )o-6-S-(CH 2 ) O -6- or a -(CH 2 ) 0 -6-linked heterocyclic group useful as. neuroprotective agents.
  • WO 2004/106325 (Schering AG) describes prodrugs of the Rho-kinase inhibitor fasudil carrying an ether or ester group in the 1 -position of the isoquinoline ring.
  • JP 10087629 A describes isoquinoline derivatives useful for the treatment of diseases caused by Helic o bacter pylori such as for example gastritis cancer or ulcer; the isoquinoline derivatives may be substituted by OH in the 1 -position and are preferably 5-substituted by X-[(C ⁇
  • I may be among others an optionally substituted isoquinolone and Ar Il may be among others optionally substituted cyclohexyl.
  • WO 2005/030791 (Merck & Co.) generically describes as potassium channel inhibitors for the treatment of cardiac arrhythmias, stroke, congestive heart failure etc. isoquinolone derivatives which are optionally substituted in 6-position by a group
  • R 43 is e.g. a (C3-C-jo)cycloalkyl residue optionally substituted by NR51 R52 wherein R ⁇ and R ⁇ 2 may be hydrogen,
  • R 43 is a group R81 defined as a 4-6 membered unsaturated or saturated monocyclic heterocylic ring with 1 , 2, 3 or 4 heteroatoms; and are substituted by a directly bound optionally substituted aryl or heteroaryl ring in the 4-position.
  • WO 2005/030130 (Merck & Co.) generically describes as potassium channel inhibitors for the treatment of cardiac arrhythmias, stroke, congestive heart failure etc. isoquinoline derivatives which may be substituted by hydroxyl in the 1 -position and are optionally substituted in 6-position by a group (CR e Rf)pOR 43 wherein p may be zero, and R 4 S is e.g.
  • R ⁇ and R 52 may be hydrogen, (Ci-C ⁇ )alkyl etc.; or R 43 is a group R 8 ⁇ defined as a 4-6 membered unsaturated or saturated monocyclic heterocylic ring with 1 , 2, 3 or 4 heteroatoms; and are substituted by a directly bound optionally substituted aryl or heteroaryl ring in the 4-position.
  • WO 03/053330 (Ube) describes isoquinolone derivatives of the formula
  • Rho-kinase inhibitors As Rho-kinase inhibitors.
  • An embodiment of the present invention is a compound of the formula (I)
  • R 2 is H, (C-i-C ⁇ Jalkyl.
  • R 3 is H, halogen, CN, (C ⁇
  • R4 is H, halogen, hydroxy, CN, (C-
  • R 5 is H, halogen, CN, NO 2 , (C ⁇
  • R ⁇ and RQ' are independently of each other H, R', (C ⁇
  • R7 and Rg are independently of each other H, halogen, CN, NO 2 , (C-j-C ⁇ Jalkyl, O-tC-i-C 6 )alkyl, O-t ⁇ -i-C 6 )alkylen ⁇ o-i-R', (C 2 -C 6 )alkenyl, R', (C 2 -C6)alkenylene-(C 6 -Cio)aryl, (C 1 -C 6 )alkylene-R 1 , NH 2 , NH-R', NH-SO 2 H, NH-SO 2 -(C «
  • Rg is halogen or (C-
  • n O, 1 , 2, 3 or 4;
  • L is O or ⁇ -(C-i-C ⁇ Jalkylene
  • R' is (C3-C8)cycloalkyl, (C5-C-
  • R" is (C 3 -C 8 )cycloalkyl, (C 5 -C 10 )heterocyclyl, (C 6 -C 10 )aryl, (C-i-C ⁇ Jalkyl, (C 1 -C 6 )alkylene-R 1 , (C-j-C 6 )alkylene-O ⁇ C-i-C 6 )alkyl, (C ⁇ C ⁇ Jalkylene-O-R', or (C 1 -C 6 )alkylene-NRxRy; and wherein R x and Ry are independently of each other (C-
  • one alkyl or alkylene hydrogen atom can optionally be substituted by OH, OCH3, COOH 1 COOCH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CONH 2 , CONHCH3 or CON(CH3) 2 or an alkyl or alkylene may be halogenated once or more;
  • one alkyl or alkylene hydrogen atom in residues R4, R5, R7 and Rg can optionally be substituted by OH, F, OCH 3 , COOH, COOCH3, NH 2 , NHCH3, N(CH 3 ) 2 , CONH 2 , CONHCH3 or CON(CH3) 2 .
  • Stereoisomeric forms of the isoquinolone derivatives of the formula (I) include the corresponding tautomeric 1-hydroxy-substituted isoquinoline derivatives of the formula
  • Ri is H, (C «
  • R3, R4, R5, RQ, RQ', RJ, RQ, Rg, n and L are as defined above.
  • R 2 in the compound of the formula (I) is H, the compound is thus characterized by a compound of the formula (II)
  • in the compound of the formula (I 1 ) is H, the compound is thus characterized by a compound of the formula (H')
  • R3 is preferably H, halogen, (Ci-Cg)alkyl, (C ⁇
  • R4 is H, halogen, CN, (Ci-Cg)alkyl, NH-(C 6 -Ci o) ar y' or (Ci-Cg)alkylene- R'. More preferably, R4 is H, halogen, (Ci-Cg)alkyl, NH-(Cg-Ci o)aryl or (Ci-Cg)alkylene-R'. In a further preferred embodiment, R4 is H, halogen, (Ci-Cg)alkyl, NH-(Cg-C-I rj)aryl or (Ci-C2)alkylene-(Cg-Cio)aryl.
  • R4 is H, halogen, or (Ci-Cg)alkyl. Especially preferred, R4 is H, halogen or (Ci-Cg)alkyl. More especially preferred, R4 is H or (Ci-Cg)alkyl. Most especially preferred, R4 is H.
  • R5 is H, halogen, CN, (Ci-Cg)alkyl, R 1 , NH-(Cg-Ci rj)aryl or (C-1-C6)alkylene-R ⁇ More preferably, R5 is H, halogen, (Ci-Cg)alkyl, R',
  • R5 is H, halogen, (C 6 -Ci 0 )aryl, NH-(C 6 -C i O )aryl, (Ci-C2)alkylene-(C 6 -C 1 0 )aryl, (Ci-Cg)alkyl or (C5-Cio)heteroaryl.
  • R5 is H, halogen, phenyl, (Ci-Cg)alkyl or (C5-Cg)heteroaryl.
  • R5 is H, halogen or (Ci-Cg)alkyl.
  • R5 is H or halogen. Most especially preferred, R5 is H.
  • Rg and Rg' are independently of each other H, (C-i-Cg)alkyl, R', (Ci-C4)alkylene-(C3-C8)cycloalkyl, (C"
  • Rg is H and Rg' is H, (C-
  • Rg and Rg' are H.
  • R6 or R6 ' are, independently from each other, hydrogen, methyl, ethyl, propyl, isopropyl, 3-methyl-butyl, 2-methyl-propyl, butyl, pentyl, 3,3,3-trifuoropropyl, 4,4,4-trifluorobutyl or a substituent selected from the group consisting of
  • R7 and Re are independently of each other H, halogen, CN, (C «
  • R7 and Rs are independently of each other H, halogen, (C-
  • Rg is preferably halogen or (C-i-C4)alkyl. More preferred, Rg is Cl, F, methyl or ethyl.
  • n is 0, 1 , 2 or 3. More preferred, n is 0 or 1. Most preferred, n is 0.
  • the linker group L may be bound to the cyclohexyl ring in any position via a cyclohexyl ring carbon atom and may thereby form the cis- or the trans-stereoisomer of a compound according to the invention.
  • L is attached to the 4-position of the cyclohexyl ring
  • L is attached to the 4-position of the cyclohexyl ring.
  • L is O-methylene, O-ethylene or O. More preferably, L is O-methylene, O- ethylene or most preferred O attached to the 4-position of the cyclohexyl ring.
  • L is O.
  • one or more or all of the groups contained in the compounds of formulae (I) or (I 1 ) can independently of each other have any of the preferred, more preferred or most preferred definitions of the groups specified above or any one or some of the specific denotations which are comprised by the definitions of the groups and specified above, all combinations of preferred definitions, more preferred or most preferred and/or specific denotations being a subject of the present invention.
  • the invention includes the compounds of the formulae (I) or (I') in all stereoisomeric forms and mixtures of stereoisomeric forms in all ratios, and/or their physiologically acceptable salts.
  • a preferred embodiment of the present invention is a compound of the formulae (I), (I 1 ), (II) or (II 1 ) wherein
  • R3 is H, halogen, CN, (C 1 -C 6 )alkyl, (Ci-C 6 )alkylene-R', OH, O-R", NH2, or NHR";
  • R4 is H, halogen, hydroxy, CN, (C 1 -C 6 )alkyl, (C3-C8)cycloalkyl, (C 1 -C 6 )alkylene-R 1 ;
  • R5 is H, halogen, CN, NO2, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, R 1 , (C 1 -C6)alkylene-(C 6 -C 1 o)aryl, (C 2 -C6)alkenylene-(C 6 -C -
  • RQ and RQ are independently of each other H, (C3-C8)cycloalkyi, (Ci-C8)alkyl, (C-i-C6)alkylene-R', (Ci-C 6 )alkylene-O-(C «
  • R7 and Rs are independently of each other H, halogen, CN, NO2, (C-
  • Rg is halogen or (C-i-C ⁇ Jalkyl; n is O, 1 , 2; and
  • L is O or 0-(C ⁇ -C2)a ⁇ ene
  • R 1 , R 2 , R', R", Rx and Ry are as defined above;
  • a further preferred embodiment of the present invention is a compound of the formulae (I), (I 1 ), (II) or (II 1 ) wherein R 3 is H, halogen, CN, (CyCQ)a ⁇ ky ⁇ , (C-i-C 66 )alkylene-R 1 or NHR";
  • R4 is H, halogen, CN 1 (C-i-C ⁇ alkyl, (C3-C8)cycloalkyl, (C-i-C 6 )alkylene-R 1 ;
  • R5 is H, halogen, CN, NO2, (C-i-C ⁇ alkyl, (C2-C6)alkenyl, R', (C 1 -C 6 )alkylene-CC 6 -CioJaryl. ⁇ -C 6 )alkenylene ⁇ C 6 -CToJaryl, (C 1 -C 6 )alkylene-(C 5 -Cio)heterocyclyl, NH2, NH-R', NH-C(O)-(C 1 -C ⁇ Jalkyl, or C ⁇ OJNKC-i-C ⁇ Jalkylfe;
  • R ⁇ and RQ' are independently of each other H, (C 3 -C8)cycloalkyl, (C-
  • R7 and Rg are independently of each other H, halogen, CN, NO2, (C-i-C ⁇ Jalkyl, (C2-C 6 )alkenyl, R', (C2-C 3 )alkenylene-(C 6 -C 10 )aryl, (Ci-C 3 )alkylene-R', NH-R', NH- SO 2 -(C 1 -C 6 )alkyl, or SO2-NH2;
  • Rg is halogen or (C-i-C ⁇ Jalkyl
  • n O or 1 ;
  • L is O or O-methylene
  • R 1 , R 2 , R', R", Rx and Ry are as defined above;
  • a most preferred embodiment of the present invention is a compound of the formulae (I), (I 1 ), (II) or (II 1 ) wherein R 3 is H, halogen, CN, (C 1 -C 6 )alkyl, (C ⁇
  • R4 is H, halogen, CN, (C-i-C 6 )alkyl, (C3-C6)cycloalkyl, (C-
  • R5 is H, halogen, CN, NO2, (C «
  • RQ is H, (C3-C 6 )cycloalkyl or (C ⁇
  • R ⁇ ' is H, (C3-C8)cycloalkyl, (C ⁇
  • R7 and Re are independently of each other H, halogen, CN, NO2, (C-
  • Rg is halogen or (C-j-C 6 )alkyl
  • , R2, R', R", Rx and Ry are as defined above;
  • R3 is H, halogen, (C ⁇
  • F*4 is H, halogen, (Ci-C4)alkyl;
  • R5 is H 1 halogen, (C-
  • RQ is H, (C3-C8)cycloalkyl, or (Ci-Cs)alkyl;
  • R 6 1 is H, (C3-C8)cycloalkyl, (C-i-CgJalkyl, or (Ci-C3)alkylene-R';
  • R7 and Re are independently of each other H, halogen, CN, (Ci-C ⁇ jalkyl or SO2-NH2;
  • Rg is halogen or (C ⁇
  • n 0 ;
  • , R2, and R' are as defined above;
  • one or more or all of the groups can have any of its preferred, more preferred, most preferred definitions specified above or any one or some of the specific denotations which are comprised by its definitions and are specified above.
  • Physiologically acceptable salts of compounds of the formulae (I) and (I 1 ) mean both their organic and inorganic salts as described in Remington's Pharmaceutical Sciences (17th edition, page 1418 (1985)).
  • acidic groups inter alia to sodium, potassium, calcium and ammonium salts
  • basic groups inter alia to salts of maleic acid, fumaric acid, succinic acid, malic acid, tartaric acid, methylsulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, for example as hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates, and salts of amino acids, of natural bases or carboxylic acids.
  • the compounds of the formula (I) form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or else basic amino acids, for example lysine, ornithine or arginine.
  • Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid.
  • inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid
  • organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic
  • Salts with a physiologically unacceptable anion such as, for example, trifluoroacetate likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
  • physiologically functional derivative refers to any physiologically tolerated derivative of a compound of the formulae (I) or (I 1 ) of the invention, for example an N-oxide, which on administration to a mammal such as, for example, a human is able to form (directly or indirectly) a compound of the formula (I) or (I') or an active metabolite thereof.
  • Physiologically functional derivatives include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not.
  • the invention relates to a compound of the formula (I) or (I 1 ) in the form of their racemates, racemic mixtures and pure enantiomers and to their diastereomers and mixtures thereof.
  • radicals or substituents may occur more than once in the compounds of the formulae (I) or (I 1 ), they may all, independently of one another, have the stated meaning and be identical or different.
  • the compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.
  • alkyl and the corresposponding alkylene substituents are understood as a hydrocarbon residue which can be linear, i.e. straight-chain, or branched and has 1 , 2, 3, 4, 5 or 6 carbon atoms, respectively, where applicable. This also applies if an alkyl group occurs as a substituent on another group, for example in an alkoxy group
  • alkyl S-alkyl or a -O(C*
  • alkyl groups are methyl, ethyl, propyl, butyl, pentyl or hexyl, the n- isomers of all these groups, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl or tert- pentyl.
  • Alkyl groups may - if not otherwise stated - be halogenated once or more, e.g. alkyl groups may be fluorinated, e.g. perfluorinated.
  • halogenated alkyl groups are CF3 and CH2CF3, OCF3, SCF ⁇ , or -O-(CF2)2-O-.
  • Halogen means fluoro, chloro, bromo or iodo.
  • (C3-C8)cycloalkyl groups are cyclic alkyl groups containing 3, 4, 5, 6, 7 or 8 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl, which can also be substituted and/or contain 1 or 2 double bonds (unsaturated cycloalkyl groups) like, for example, cyclopentenyl or cyclohexenyl can be bound via any carbon atom.
  • o)aryl group means an aromatic ring or a ring system which comprises two aromatic rings which are fused or otherwise linked, for example a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralon-, indanyl- or indan-1-on-yl group.
  • a preferred (Cg-C 10 )aryl group is phenyl.
  • a (C5-Cio) ne terocyclyl group means a mono- or bicyclic ring system which comprises, apart from carbon, one or more heteroatoms such as, for example, e.g. 1 , 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or combinations of different hetero atoms.
  • the heterocyclyl residues can be bound at any positions, for example on the 1 -position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8- position.
  • Suitable (C5-Cio)heterocyclyl groups include acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzomorpholinyl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, furanyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, chromen-2-onyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuran, furyl
  • Pyridyl stands both for 2-, 3- and 4-pyridyl.
  • Thienyl stands both for 2- and 3-thienyl.
  • Furyl stands both for 2- and 3-furyl.
  • N-oxides of these compounds for example, 1-oxy-2-, 3- or 4-pyridyl.
  • Preferred examples of (C5-Cio)heterocyclyl residues are pyrazinyl, pyridyl, pyrimidinyl, pyrazolyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, thienyl, benzofuryl, quinolinyl, tetrazolyl and triazolyl.
  • (C ⁇ -C-i o)aryl and (C5-Cirj) neter ocyclyl groups are unsubstituted or, if not otherwise stated, substituted one or more times by suitable groups independently selected from halogen, CF3, NO2, N3, CN 1 C(O)-(C 1 -C 6 )alkyl.
  • Aryl or heterocyclyl substituents of (C 6 -C 1 o)aryl and (C 5 -C 1 o)heterocyclyl groups may not be further substituted by an aryl or hetero
  • substituents for (C 6 -C 10 )aryl groups are (C-
  • o)aryl are halogen, (C-
  • the substituent can be located in the 2-position, the 3-position or the 4-position, with the 3-position and the 4-position being preferred. If a phenyl group carries two substituents, they can be located in 2, 3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In phenyl groups carrying three substituents the substituents can be located in 2,3,4-position, 2,3,5-position, 2,3,6- position, 2,4,5-position, 2,4,6-position, or 3,4,5-position.
  • phenyl groups correspondingly apply to divalent groups derived from phenyl groups, i.e. phenylene which can be unsubstituted or substituted 1 ,2-phenylene, 1 ,3-phenylene or 1 ,4-phenylene.
  • the above statements also correspondingly apply to the aryl subgroup in arylalkylene groups.
  • arylalkylene groups which can also be unsubstituted or substituted in the aryl subgroup as well as in the alkylene subgroup, are benzyl, 1-phenylethylene, 2-phenylethylene, 3- phenylpropylene, 4-phenylbutylene, 1-methyl-3-phenyl-propylene.
  • More preferred substituents for (C5-C ⁇ jrj)heterocyclyl groups are (C ⁇
  • rj)heterocyclyl groups may be combined with the general and preferred definitions of R ⁇ , R2, R3, R4, R5.
  • the present invention therefore also relates to the compounds of the formulae (I) or (I 1 ) and/or their physiologically acceptable salts and/or stereoisomer ⁇ forms for use as pharmaceuticals (or medicaments), to the use of the compounds of the formulae (I) or (I 1 ) and/or their physiologically acceptable salts and/or stereoisomeric forms for the production of pharmaceuticals for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, i.e.
  • hypertension for the treatment and/or prevention of hypertension, pulmonary hypertension, ocular hypertension, retinopathy, and glaucoma, peripheral circulatory disorder, peripheral occlusive arterial disease (PAOD), coronary heart disease, angina pectoris, heart hypertrophy, heart failure, ischemic diseases, ischemic organ failure (end organ damage), fibroid lung, fibroid liver, liver failure, nephropathy, including hypertension-induced, non-hypertension-induced, and diabetic nephropathies, renal failure, fibroid kidney, renal glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, e.g.
  • PAOD peripheral occlusive arterial disease
  • COPD chronic obstructive pulmonary disease
  • neuropathic pain neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes and complications of diabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy such as osteoporosis, infection of digestive tracts with bacteria, sepsis, cancer development and progression, e.g. cancers of the breast, colon, prostate, ovaries, brain and lung and their metastases.
  • the treatment and/or prevention of diseases in humans is a preferred embodiment but also warm blooded animals such as cats, dogs, rats, horses etc. may be treated with the compounds of the present invention.
  • the present invention furthermore relates to pharmaceutical preparations (or pharmaceutical compositions) which contain an effective amount of at least one compound of the formula (I) or (I 1 ) and/or its physiologically acceptable salts and/or stereoisomeric forms and a pharmaceutically acceptable carrier, i. e. one or more pharmaceutically acceptable carrier substances (or vehicles) and/or additives (or excipients).
  • physiologically functional derivatives including the prodrugs, of a compound of the formula (I) or (I') may be utilized in the above mentioned uses and pharmaceutical preparations.
  • the pharmaceuticals can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures.
  • Administration can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
  • compositions according to the invention are prepared in a manner known per se and familiar to one skilled in the art, pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or additives being used in addition to the compound(s) of the formulae (I) or (I 1 ) and/or its (their) physiologically acceptable salts and/or its (their) stereisomeric forms as well as its (their) prodrugs.
  • pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or additives being used in addition to the compound(s) of the formulae (I) or (I 1 ) and/or its (their) physiologically acceptable salts and/or its (their) stereisomeric forms as well as its (their) prodrugs.
  • pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or additives being used in addition to the compound(s) of the formulae (I) or (I 1 ) and/or its (their) physiologically acceptable salts and/or its
  • Carrier substances for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc.
  • Suitable carrier substances for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc.
  • Suitable carrier substances for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid.
  • the pharmaceutical preparations normally contain about 0.5 to about 90 % by weight of a compound of the formula (I) or (I 1 ) and/or their physiologically acceptable salts and/or their stereisomeric forms.
  • the amount of the active ingredient of the formula (I) or (I 1 ) and/or its physiologically acceptable salts and/or its stereisomeric forms in the pharmaceutical preparations normally is from about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg.
  • the pharmaceutical preparations can contain one or more additives such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.
  • additives such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants.
  • the pharmaceutical preparations can also contain two or more compounds of the formulae (I) and/or (I 1 ) and/or their physiologically acceptable salts and/or their prodrugs.
  • a pharmaceutical preparation contains two or more compounds of the formulae (I) and/or (I 1 )
  • the selection of the individual compounds can aim at a specific overall pharmacological profile of the pharmaceutical preparation. For example, a highly potent compound with a shorter duration of action may be combined with a long-acting compound of lower potency.
  • the flexibility permitted with respect to the choice of substituents in the compounds of the formulae (I) or (I 1 ) allows a great deal of control over the biological and physico-chemical properties of the compounds and thus allows the selection of such desired compounds.
  • the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.
  • the dose can vary within wide limits and, as is customary and is known to the physician, is to be suited to the individual conditions in each individual case. It depends, for example, on the specific compound employed, on the nature and severity of the disease to be treated, on the mode and the schedule of administration, or on whether an acute or chronic condition is treated or whether prophylaxis is carried out.
  • An appropriate dosage can be established using clinical approaches well known in the medical art.
  • the daily dose for achieving the desired results in an adult weighing about 75 kg is from about 0.01 to about 100 mg/kg, preferably from about 0.1 to about 50 mg/kg, in particular from about 0.1 to about 10 mg/kg, (in each case in mg per kg of body weight).
  • the daily dose can be divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations. As usual, depending on individual behavior it may be necessary to deviate upwards or downwards from the daily dose indicated.
  • the compounds of the formulae (I) or (I 1 ) can be used as synthesis intermediates for the preparation of other compounds, in particular of other pharmaceutical active ingredients, which are obtainable from the compounds of the formula I, for example by introduction of substituents or modification of functional groups.
  • protective groups that may still be present in the products obtained in the coupling reaction are then removed by standard procedures.
  • tert-butyl protecting groups in particular a tert-butoxycarbonyl group which is a protection form of an amino group
  • tert-butoxycarbonyl group which is a protection form of an amino group
  • functional groups can be generated from suitable precursor groups.
  • a conversion into a physiologically acceptable salt or a prodrug of a compound of the formulae (I) or (I 1 ) can then be carried out by known processes.
  • a reaction mixture containing a final compound of the formula (I) or (I 1 ) or an intermediate is worked up and, if desired, the product is then purified by customary processes known to those skilled in the art.
  • a synthesized compound can be purified using well known methods such as crystallization, chromatography or reverse phase-high performance liquid chromatography (RP-HPLC) or other methods of separation based, for example, on the size, charge or hydrophobicity of the compound.
  • RP-HPLC reverse phase-high performance liquid chromatography
  • well known methods such as amino acid sequence analysis, NMR, IR and mass spectrometry (MS) can be used for characterizing a compound of the invention.
  • Isoquinolinones can by synthesized via a variety of methods.
  • the following general schemes illustrate some of the possible ways to access isoquinolones, but do not limit the present invention.
  • a suitably substituted aldehyde for example substituted by X or Y being independently from each other hydrogen, alkyl, alkoxy or halide attached in a suitable position, can be reacted with a suitable compound such as for example an actal of aminoacetaldehyde for example in a solvent like THF, chloroform or toluene under acid catalysis by toluene sulfonic acid or another appropriate acid to give imine (ii) wherein Q' can be for instance methyl or ethyl, which in turn can be cyclized by different methods to the isoquinoline (iii).
  • a suitable compound such as for example an actal of aminoacetaldehyde for example in a solvent like THF, chloroform or toluene under acid catalysis by toluene sulfonic acid or another appropriate acid to give imine (ii) wherein Q' can be for instance methyl or ethyl, which in turn can be cyclized by different methods
  • this can be done by Lewis acid catalysis by suitable Lewis acids like titanium tetrachloride, ferrous halides, aluminium halides etc. at temperatures ranging from ambient to 100 0 C or by reducing the imine to the corresponding amine by action of a suitable reducing agent like sodium borohydride, converting the amine into an amide or sulphonamide by reaction with a suitable acid chloride and subsequent cyclization to the isoquinoline by action of an appropriate lewis acid.
  • the isoquinoline (iii) itself can then be converted to the corresponding N- oxide (iv) by action of a suitable oxidative agent like hydrogen peroxide, m-chloro perbenzoic acid or others at room temperature or elevated temperature.
  • the N-oxide (iv) can then be converted into the 1-chloro-isoquinoline derivative (v) by reacting it with a reagent like phosphorous oxy chloride in or without presence of phosphorous pentachloride.
  • the derivative (v) can then be turned into suitable 1 -alkoxy-derivatives by reacting it with various alcohols Q-OH like methanol, ethanol or benzyl alcohol in the presence of a suitable base like sodium hydride and in a suitable solvent like dimethyl formamide, dimethyl acetamide or others.
  • (v) can be directly converted into the isoquinolinone derivative (vii) by reacting it with a reagent like ammonium acetate.
  • isoquinolines can be obtained by reacting suitable 3-formylated or acylated fluorobenzenes (viii), wherein z is for example H or alkyl like methyl or ethyl, with a reagent like triethyl phosphono acetate in the presence of a suitable base like sodium hydride to give the corresponding cinnamic acid ester, which subsequently is cleaved by action of a suitable base like potassium hydroxide, sodium hydroxide or lithium hydroxide in a suitable solvent to deliver acid (ix).
  • a suitable base like potassium hydroxide, sodium hydroxide or lithium hydroxide in a suitable solvent to deliver acid (ix).
  • (ix) can then be converted in the corresponding acid chloride by well known methods, which can be transferred into the acid azide by reaction with sodium azide in a suitable solvent like ether, chloroform or acetone in or without the presence of water.
  • the corresponding azide then can be converted into isoquinolinone (x) by reacting it in a suitable solvent like diphenylmethane or dipenylether at suitable temperature.
  • Isoquinolone derivatives like (xii) can be obtained as free bases or as various salts like for example hydrochlorides, hydrobromides, phosphates, trifluoroacetates, sulfates or fumarates.
  • the salts obtained can be converted into the corresponding free base by either subjecting them to ion exchange chromatography or for example by alkaline aqueous treatment and subsequent extraction with suitable organic solvents like for example methyl tert. butyl ether, chloroform, ethyl acetate or isopropanol / dichloromethane mixtures and subsequent evaporation to dryness.
  • N-[4-(2-Oxy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (17) was converted to the title compound following the protocol described for 1 ,7-dichloro-6-fluoro-isoquinoline (6).
  • Boc-protected products were deprotected during the evaporation of the HPLC-product fractions, which contained 0.1% TFA, or during the subsequent stirring in 2 N HCI/Methanol.
  • the protected starting compounds were heated in TFA in a microwave oven at 140 0 C until complete conversion was observed. Evaporation of the solvent and purification by preparative HPLC gave the desired deprotected products as trifluoroacetates, which were dissolved in 2 N HCI and evaporated. After dissolving the residue in water and lyophilization, the compounds were isolated as HCI-salts.
  • a reaction mixture consisting of 150 mg (0.49 mmol) 6-(cis-4-amino-cyclohexyloxy)-7- methyl-2H-isoquinolin-1-one hydrochloride (example 138), 38 mg (0.63 mmol) of acetic acid, 43 mg (0.97 mmol) of acetaldehyde, molecular sieves and 515 mg (2.4 mmol) of sodium triacetoxy borohydride in 5 ml of methylene chloride was stirred overnight. The reaction mixture was added to 10 ml of 1 M sodium hydroxide solution and extracted twice with a mixture of methylene chloride and isopropanol.
  • the acid chloride was dissolved in 45 mL of acetone. At 0 0 C 8.03 g of NaN 3 (123.5 mmol, 2 eq.) were added portionwise. Then 41 mL of water were added while the temperature was kept below 5 0 C. The reaction was stirred for another 1.5 h. Then 55 ml of chloroform were added. The mixture was extracted with 80 mL of water followed by 40 mL of brine. After drying over Na 2 SO4 and filtration 14 mL of diphenyl ether were added and most of the chloroform was removed in vacuo (without heating). A total removal of the chloroform should be avoided.
  • Method B Stationary phase: CoI YMC Jsphere 33 x 2 Gradient: ACN+0,05% TFA : H 2 O + 0.05% TFA 5:95(0 min) to 95:5(2.5 min) to 95:5(3.0 min)
  • IC50 values were determined according to the following protocol: Buffer: 25mM Tris pH7.5; 0.02% BSA; 5% Glycerol; 0.008% Triton X100; 2% DMSO, 1mM DTT; 1mM MgCI 2 ; 0.5 ⁇ Ci/well ⁇ 33 P ATP Enzyme: ROCKII or ROK ⁇ ) (Upstate, Catalog # 14-451) 0.1 ng/ ⁇ l Final concentration of ATP in reaction mixture 40 ⁇ M Biotinylated substrate, diluted to 0.25 ⁇ M with buffer described above (without ATP)
  • PIC50 negative decadal logarithm of the IC50

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Diabetes (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pulmonology (AREA)
  • Rheumatology (AREA)
  • Endocrinology (AREA)
  • Biomedical Technology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Oncology (AREA)
  • Urology & Nephrology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Communicable Diseases (AREA)
  • Pain & Pain Management (AREA)
  • Gynecology & Obstetrics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Reproductive Health (AREA)
  • Virology (AREA)
  • Psychiatry (AREA)
  • Molecular Biology (AREA)

Abstract

The invention relates to 6-cyclohexylamine-substituted isoquinolone derivatives of the formula (I) or isoquinoline derivatives of the formula (I’) useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, and compositions containing such compounds.

Description

CYCLOHEXYLAMIN ISOQUINOLONE DERIVATIVES AS RHO-KINASE INHIBITORS
The present invention relates to novel isoquinolone and isoquinoline derivatives as described in the claims, their preparation and their use in the treatment and/or prevention of diseases related to the inhibition of Rho-kinase and/or of Rho-kinase mediated phosphorylation of myosin light chain phosphatase.
Activation of a small GTPase RhoA upon agonist stimulation results in conversion of RhoA from the inactive GDP-bound form to the active GTP-bound form with a subsequent binding to and activation of Rho-kinase. Two isoforms, Rho-kinase 1 and Rho-kinase 2, are known. Rho-kinase 2 is expressed in vascular smooth muscle cells and endothelial cells. Activation of Rho-kinase 2 by the active GTP-bound RhoA leads to calcium sensitization of smooth muscle cells through phosphorylation-mediated inhibition of the myosin light chain phosphatase activity and thereby up-regulation of the activity of myosin regulatory light chain (Uehata et al., Nature 1997, 389, 990-994).
It is known that Rho-kinase is involved in vasoconstriction, including the development of myogenic tone and smooth muscle hypercontractility (Gokina et al. J. Appl. Physiol. 2005, 98, 1940-8), bronchial smooth muscle contraction (Yoshii et al. Am. J. Resp. Cell MoI. Biol. 20, 1190-1200), asthma (Setoguchi et al. Br J Pharmacol. 2001 , 132,111-8; Nakahara, et al. Eur J 2000,389,103) and chronic obstructive pulmonary disease (COPD, Maruoka, Nippon Rinsho, 1999 , 57, 1982-7), hypertension, pulmonary hypertension (Fukumoto et al. Heart, 91 , 391-2, 2005, Mukai et al. Nature 1997,389, 990-4 ) and ocular hypertension and regulation of intraoccular pressure (Honjo et al. Invest. Ophthalmol. Visual Sci. 2001 , 42, 137-144), endothelial dysfunction (Steioff et al. Eur. J. Pharmacol. 2005, 512, 247-249), angina (Masumoto et al. Circ 2002, 105, 1545-47, Shimokawa et al. JCP, 2002, 40, 751-761), nephropathy, including hypertension-induced, non-hypertension-induced, and diabetic nephropathies, renal failure and peripheral occlusive arterial disease (PAOD) (Wakino et al. Drug News Perspect. 2005, 18, 639-43), myocardial infarction (Demiryurek et al. Eur J Pharmacol. 2005, 527, 129-40, Hattori et al. Circulation, 2004, 109,2234-9), cardiac hypertrophy and failure (Yamakawa, et al. Hypertension 2000, 35, 313-318, Liao et al. Am J Physiol Cell Physiol. 2006, 290, C661-8, Kishi et al. Circ 2005, 111 , 2741-2747), coronary heart disease, artherosclerosis, restenosis (Pacaud et al. Arch. MaI. Coeur 2005, 98, • 249-254, Retzer, et al. FEBS Lett 2000,466,70, Negoro, et al. Biochem Biophys Res Commun 1999,262, 211), diabetes, diabetic complications, glucose utilization and metabolic syndrome (Sandu, et al.Diabetes 2000,49,2178, Maeda et al. Cell Metab. 2005, 2, 119-29), sexual dysfunction, e.g., penile erectile dysfunction (Chitaley et al. Nature Medicine 2001 , 7, 119-122), retinopathy, inflammation, immune diseases, AIDS, osteoporosis, endocrine dysfunctions, e.g. hyperaldosteronism, central nervous system disorders such as neuronal degeneration and spinal cord injury (Hara, et al. JNeurosurg 2000, 93, 94), cerebral ischemia (Uehata, et al. Nature 1997,389,990; Satoh et al. Life Sci. 2001 , 69, 1441-53; Hitomi, et al. Life Sci 2000,67,1929; Yamamoto, et al. J Cardiovasc Pharmacol. 2000, 35, 203-11), cerebral vasospasm (Sato, et al. Circ Res 2000,87,195; Kim, et al. Neurosurgery 2000,46,440), pain, e.g. neuropathic pain (Tatsumi, et al. Neuroscience 2005, 131 ,491 , Inoue, et al. Nature medicine 2004, 10, 712), infection of digestive tracts with bacteria (WO 98/06433), cancer development and progression, neoplasia where inhibition of Rho kinase has been shown to inhibit tumor cell growth and metastasis (Itoh, et al. Nature Medicine 1999,5,221 ; Somlyo, et al. Res Commun 2000,269,652), angiogenesis (Uchida, et al. Biochem Biophys Res 2000, 269,633-40 ; Gingras, et al. Biochem J 2000, 348,273), vascular smooth muscle cell proliferation and motility (Tammy et al. Circ. Res. 1999, 84, 1186-1193; Tangkijvanich et al. Atherosclerosis 2001 , 155, 321-327), endothelial cell proliferation, endothelial cell retraction and motility (Oikawa et al. Biochem. Biophys. Res. Commun. 2000, 269, 633-640), stress fiber formation (Kimura et al. Science 1997, 275, 1308-1311 ; Yamashiro et al. J. Cell Biol. 2000, 150, 797-806), thrombotic disorders (Kikkawa, et al. FEBS Lett. 2000, 466, 70-74; Bauer et al. Blood 1999, 94, 1665-1672, Klages, et al. J Cell Biol 1999,144, 745; Retzer, et al. Cell Signal 2000,12,645) and leukocyte aggregation (Kawaguchi, et al. Eur J Pharmacol. 2000, 403:203-8; Sanchez-Madrid, et al. J Immunol. 2003, 171 :1023-34, Sanchez-Madrid, et al. J Immunol. 2002, 168:400-10), and bone resorption (Chellaiah, et al. J Biol Chem. 2003, 278:29086-97). Na/H exchange transport system activation (Kawaguchi, et al. Eur J Pharmacol. 2000, 403:203-8), Alzheimer's disease (Zhou et al. Science 2003, 302, 1215-1217), adducin activation (Fukata et al. J. Biol. Chem., 1998, 273, 5542- 5548), and in SREB (Sterol response binding element) signalling and its effects on lipid metabolism (Lin et al. Circ. Res., 92, 1296-304, 2003).
Therefore, a compound having inhibitory effect on Rho-kinase and/or on Rho-kinase mediated phosphorylation of myosin light chain phosphatase is useful for the treatment and/or prevention of cardiovascular and non-cardiovascular diseases involving Rho- kinase as the primary or secondary disease cause, like hypertension, pulmonary hypertension, ocular hypertension, retinopathy, and glaucoma, peripheral circulatory disorder, peripheral occlusive arterial disease (PAOD), coronary heart disease, angina pectoris, heart hypertrophy, heart failure, ischemic diseases, ischemic organ failure (end organ damage), fibroid lung, fibroid liver, liver failure, nephropathy, including hypertension-induced, non-hypertension-induced, and diabetic nephropathies, renal failure, fibroid kidney, renal glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, e.g. neuropathic pain, neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes and complications of diabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy such as osteoporosis, infection of digestive tracts with bacteria, sepsis, cancer development and progression, e.g. cancers of the breast, colon, prostate, ovaries, brain and lung and their metastases.
WO 01/64238 describes isoquinoline-5-sulfonamide derivatives optionally substituted by a -(CH2)i-6-0-(CH2)o-6-. a -(CH2)o-6-S-(CH2)O-6- or a -(CH2)0-6-linked heterocyclic group useful as. neuroprotective agents.
WO 2004/106325 (Schering AG) describes prodrugs of the Rho-kinase inhibitor fasudil carrying an ether or ester group in the 1 -position of the isoquinoline ring.
WO 2001/039726 generically describes -0-(CQ-C <|o)alkyl-heteroaryl substituted cyclohexyl derivatives useful for the treatment of microbial infections. JP 10087629 A describes isoquinoline derivatives useful for the treatment of diseases caused by Helicobacter pylori such as for example gastritis cancer or ulcer; the isoquinoline derivatives may be substituted by OH in the 1 -position and are preferably 5-substituted by X-[(C<|-C6)alkylene)]n.-1-Y wherein X may be oxygen and Y may be an aryl or a heterocyclic group.
Yoshida et al. (Bioorg. Med. Chem. 1999, 7, 2647-2666) disclose 6-benzyloxy- isoquinoline for the treatment of infections caused by Heliobacter pylori.
US 5,480,883 generically discloses as EGF and/or PDGF receptor inhibitors useful for inhibiting cell proliferation compounds of the formula "Ar I - X - Ar II" wherein X may be (CHR-i )m-Z-(CHR-|)n, e.g. Z-CH2, wherein Z may be O, R-| is hydrogen or alkyl, Ar
I may be among others an optionally substituted isoquinolone and Ar Il may be among others optionally substituted cyclohexyl.
WO 2005/030791 (Merck & Co.) generically describes as potassium channel inhibitors for the treatment of cardiac arrhythmias, stroke, congestive heart failure etc. isoquinolone derivatives which are optionally substituted in 6-position by a group
(CReRf)pOR43 wherein p may be zero, and R43 is e.g. a (C3-C-jo)cycloalkyl residue optionally substituted by NR51 R52 wherein R^and R^2 may be hydrogen,
(Ci-Cβ)alkyl etc.; or R43 is a group R81 defined as a 4-6 membered unsaturated or saturated monocyclic heterocylic ring with 1 , 2, 3 or 4 heteroatoms; and are substituted by a directly bound optionally substituted aryl or heteroaryl ring in the 4-position.
WO 2005/030130 (Merck & Co.) generically describes as potassium channel inhibitors for the treatment of cardiac arrhythmias, stroke, congestive heart failure etc. isoquinoline derivatives which may be substituted by hydroxyl in the 1 -position and are optionally substituted in 6-position by a group (CReRf)pOR43 wherein p may be zero, and R4S is e.g. a (C3-C-|o)cycloa|ky' residue optionally substituted by NR51 R^1 wherein R^and R52 may be hydrogen, (Ci-Cβ)alkyl etc.; or R43 is a group R8^ defined as a 4-6 membered unsaturated or saturated monocyclic heterocylic ring with 1 , 2, 3 or 4 heteroatoms; and are substituted by a directly bound optionally substituted aryl or heteroaryl ring in the 4-position.
WO 03/053330 (Ube) describes isoquinolone derivatives of the formula
as Rho-kinase inhibitors.
An embodiment of the present invention is a compound of the formula (I)
wherein
R2 is H, (C-i-CβJalkyl.
[(C1 -C6)alkylene]θ-1 -O-(C <| -C6)alkyl, [(C <| -C6)alkylene]θ-1 -O-R", [(C 1 -C6)alkylene]0- 1-NH2l [(C1-C6)alkylene]o-i-NH(C1-C6)alkylI [(C1-C6)alkylene]o-i-N[(C1-C6)alkyl]2, [(Ci-C6)alkylenelo-i-CHtR1^,
[(C1-C6)alkylene]o.i-C(O)-R', [(C1-C6)alkylene]o.i-C(O)NH2, [(C1-C6)alkylene]o-1-C(O)NH-R', or [(C1-C6)alkylene]o_i-C(O)N[R']2 ;
R3 is H, halogen, CN, (C<|-C6)alkyl, (C<|-C6)alkylene-R\ OH, O-R", NH2, NHR", NR11R" or NH-C(O)-R",
R4 is H, halogen, hydroxy, CN, (C-|-C6)alkyl, (C3-C8)cycloalkyl, (Ci-C6)alkylene-R1; R5 is H, halogen, CN, NO2, (C<|-C6)alkyl, (C2-C6)alkenyl, R', (C 1 -C6)alkylene-(C6-C <| o)aryl, (C2-C6)alkenylene-(C6-C 1 o)aryl, (C1-C6)alkylene-CCs-C^heterocyclyl, NH2, NH-R', NH-SO2H1 NH-SO2-(C1 -C6)alkyl, NH-SO2-R', NH-C(O)-(Ci-C6)alkyl, NH-C(O)-R', C(O)N[(C1-C6)alkyl]2, C(O)OH or C(O)O-(C -i -C6)alkyl;
Rø and RQ' are independently of each other H, R', (C<|-C8)alkyl, (C-|-C6)alkylene-R', (C1-C6)alkylene-O^C-i-C6)alkyl, (C1-C6)alkylene-O-R', (C1-C6)alkylene-CHIR1^, (C1-C6)alkylene-C(O)-R\ (Ci-C6)alkylene-C(O)NH2, (Ci-C6)alkylene-C(O)NH-R', or (C-i-CβJalkylene-CtOMR'k;
R7 and Rg are independently of each other H, halogen, CN, NO2, (C-j-CβJalkyl, O-tC-i-C6)alkyl, O-t^-i-C6)alkylen^o-i-R', (C2-C6)alkenyl, R', (C2-C6)alkenylene-(C6-Cio)aryl, (C1-C6)alkylene-R1, NH2, NH-R', NH-SO2H, NH-SO2-(C«|-C6)alkyl, NH-SO2-R', SO2-NH2, SO2-NHR', NH-C(O)-(C1 -C6)alkyl, NH- C(O)-R', C(O)N[(C1 -C6)alkyl]2, C(O)OH or C(O)OKC-i-CβJalkyl;
Rg is halogen or (C-|-C6)alkyl;
n is O, 1 , 2, 3 or 4; and
L is O or ©-(C-i-CβJalkylene;
wherein R' is (C3-C8)cycloalkyl, (C5-C-|o)heterocyclyl or (C6-C1 rj)aryl; and
R" is (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C6-C10)aryl, (C-i-CøJalkyl, (C1-C6)alkylene-R1, (C-j-C6)alkylene-O^C-i-C6)alkyl, (C^CβJalkylene-O-R', or (C1-C6)alkylene-NRxRy; and wherein Rx and Ry are independently of each other (C-|-Cg)alkyl, (C5-C<ιo)heterocyclyl, (C6-C<|n)aryl, (C-|-C4)alkylene-(C5-Cio)heterocyclyl, (Ci-C4)alkylene-(C6-Cio)aryl, (Ci-C4)alkylene-NH(C1-C6)alkyl,
(Ci-C4)alkylene-N[(C1-C6)alkyl]2, (Ci-C4)alkylene-N[(C6-Cio)aryl]2. or (C-|-C4)alkylene-N[(C5-C-)o)heterocyclyl]2; and
wherein in residues R4, Rs, R7 and R3 one alkyl or alkylene hydrogen atom can optionally be substituted by OH, OCH3, COOH1 COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)2 or an alkyl or alkylene may be halogenated once or more;
or their pharmaceutically acceptable salts and/or stereoisomer^ forms and/or physiologically functional derivatives.
In another embodiment of a compound of formula (I) in residues R4, R5, R7 and Rg one alkyl or alkylene hydrogen atom can optionally be substituted by OH, F, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)2.
Stereoisomeric forms of the isoquinolone derivatives of the formula (I) include the corresponding tautomeric 1-hydroxy-substituted isoquinoline derivatives of the formula
(I1)
wherein Ri is H, (C«|-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, [(C1-C6)alkylene]o-1-(C3-C8)cycloalkyl, [(C-i-CβJalkylenelo-i-CCs-CioJheterocyclyl, [(C1-C6)alkylene]o-1-(C6-C10)aryl, C(O)-(C1 -C6)alkyl, C(O)(C2-C6)alkenyl, C(O)-(C2-C6)alkynyl, C(OH(Ci -C6)alkylene]o-i-(C-3-C8)cycloalkyl, C(O)-[(C 1-C6)alkylene]o-1-(C5-Cio)heterocyclyl, or C(O)-KCi-C6)alkyleneJo-i^Cβ-C^Jaryl. and wherein R3, R4, R5, RQ, RQ', RJ, RQ, Rg, n and L are as defined above. In a preferred embodiment, R2 in the compound of the formula (I) is H, the compound is thus characterized by a compound of the formula (II)
In a further preferred embodiment, R<| in the compound of the formula (I1) is H, the compound is thus characterized by a compound of the formula (H')
The compounds (II) and (H') are tautomeric forms of each other.
For example the compound having the formula
is a tautomeric form of the compound with the formula
The following preferred embodiments refer to the compounds of the formulae (I), (I1), (II) and (II1):
R3 is preferably H, halogen, (Ci-Cg)alkyl, (C<|-C4)alkylene-R\ O-R" or NHR". More preferred, R3 is H, (Ci-Cg)alkyl or NHR". Most preferred, R3 is H, (Ci-C4)alkyl, NH-(C5-C6)heterocyclyl or NH-phenyl, especially preferred R3 is H, (Ci-C4)alkyl, NH- (C5-C6)heteroaryl containing one or more N atoms or NH-phenyl. Most especially preferred, R3 is H.
Preferably, R4 is H, halogen, CN, (Ci-Cg)alkyl, NH-(C6-Ci o)ary' or (Ci-Cg)alkylene- R'. More preferably, R4 is H, halogen, (Ci-Cg)alkyl, NH-(Cg-Ci o)aryl or (Ci-Cg)alkylene-R'. In a further preferred embodiment, R4 is H, halogen, (Ci-Cg)alkyl, NH-(Cg-C-I rj)aryl or (Ci-C2)alkylene-(Cg-Cio)aryl. Most preferred, R4 is H, halogen, or (Ci-Cg)alkyl. Especially preferred, R4 is H, halogen or (Ci-Cg)alkyl. More especially preferred, R4 is H or (Ci-Cg)alkyl. Most especially preferred, R4 is H.
Preferably, R5 is H, halogen, CN, (Ci-Cg)alkyl, R1, NH-(Cg-Ci rj)aryl or (C-1-C6)alkylene-R\ More preferably, R5 is H, halogen, (Ci-Cg)alkyl, R',
NH-(Cg-Ci o)aryl or (Ci-Cg)alkylene-R'. In a further preferred embodiment, R5 is H, halogen, (C6-Ci0)aryl, NH-(C6-C iO)aryl, (Ci-C2)alkylene-(C6-C1 0)aryl, (Ci-Cg)alkyl or (C5-Cio)heteroaryl. Most preferred, R5 is H, halogen, phenyl, (Ci-Cg)alkyl or (C5-Cg)heteroaryl. Especially preferred, R5 is H, halogen or (Ci-Cg)alkyl. More especially preferred, R5 is H or halogen. Most especially preferred, R5 is H. Preferably, Rg and Rg' are independently of each other H, (C-i-Cg)alkyl, R', (Ci-C4)alkylene-(C3-C8)cycloalkyl, (C"|-C4)alkylene-(C5-C-|o)heterocyclyl, (Ci-C4)alkylene-C(0)-(C5-Cio)heterocyclyl, (Ci-C-4)alkylene-C(0)-(Cg-Cio)aryl or (C'|-C6)alkylene-(C6-Cio)ary|- ln a further preferred embodiment, Rg and Rg' are independently of each other H, (C-|-Cg)alkyl, (C5-C-io)neterocyclyl, (C3-C8)cycloalkyl, (Ci-C4)alkylene-(C3-C8)cycloalkyl, (C-|-C4)alkylene-(C5-Cio)heterocyclyl or (C-|-C6)alkylene-(C6-Cio)ary'- ln a more preferred embodiment, RQ is H, (C-|-Cg)alkyl, (C-3-C6)cycloalkyl or (C<|-C4)alkylene-(C3-Cg)cycloalkyl, and RQ' is H, (C<j-Cg)alkyl, (C3-C8)cycloalkyl, (C<| -C4)alkylene-(C3-C8)cycloalkyl, (C5-C1 o)heterocyclyl, (C-|-C4)alkylene-(C5-Cio)neterocyclyl or (C-i-CgJalkylene^Cg-C-io^ry'- 'n a further more preferred embodiment, RQ is H, (Ci-Cg)alkyl and RQ' is H, (C<|-C6)alkyl, (C3-C8)cycloalkyl, (Ci-C4)alkylene-(C3-C8)cycloalkyl, (C5-Cio)heterocyclyl, (Ci-C4)alkylene-(C5-Cio)neterocyclyl or In a further even more preferred embodiment, RQ is H, (Ci-Cβ)alkyl and RQ' is H, (C-j-Cg)alkyl, (C3-C8)cycloalkyl, (C<|-C4)alkylene-(C-3-C8)cycloalkyl,
(C-i-C4)alkylene-(C5-Cio)heterocyc'y| in which heterocyclyl is unsubstituted or substituted by (C-|-C4)alkyl or halogen, or is (C-|-Cg)alkylene-(C5-Cio)ai7l in which aryl is unsubstituted or substituted by halogen, (Ci-C4)alkyl especially CH3 or CF3, O- (C-|-C4)alkyl especially O-CH3( or SO2-(C-|-C4)alkyl especially SO2-CH3 or SO2- CF3 In a most preferred embodiment, RQ is H, (C-|-C6)alkyl and RQ' is H, (C-|-
Cβjalkyl, (C3-C8)cycloalkyl, In a further most preferred embodiment, Rg is H and Rg' is H, (C-|-Cg)alkyl, (C3-C8)cycloalkyl. Especially preferred, Rg and Rg' are H.
As examples for these embodiments, R6 or R6' are, independently from each other, hydrogen, methyl, ethyl, propyl, isopropyl, 3-methyl-butyl, 2-methyl-propyl, butyl, pentyl, 3,3,3-trifuoropropyl, 4,4,4-trifluorobutyl or a substituent selected from the group consisting of
Preferably, R7 and Re are independently of each other H, halogen, CN, (C«|-C6)alkyl, O-(C-|-C6)alkyl, (C2-C6)alkenyl, R1 or (C-|-C6)alkylene-(C3-Cs)cycloalkyl. More preferred, R7 and Rs are independently of each other H, halogen, CN, (C-|-C4)alkyl, O-(Ci-C4)alkyl, (C2-C4)alkenyl, phenyl, (C-3-C6)cycloalkyl, (C-|-C4)alkylene- (C3-C6)cycloalkyl or (C5-Cβ)heteroaryl. Even more prefered, R7 and Rs are independently of each other H, halogen, (C-|-C4)alkyl, O-(C-|-C4)alkyl or (C3-C6)cycloalkyl. Most preferably, R7 is H, halogen, (Ci-C4)alkyl or (C3-C6)cycloalky and Rs is H. Especially preferred, R7 and Rs are H.
Rg is preferably halogen or (C-i-C4)alkyl. More preferred, Rg is Cl, F, methyl or ethyl.
Preferably, n is 0, 1 , 2 or 3. More preferred, n is 0 or 1. Most preferred, n is 0.
The linker group L may be bound to the cyclohexyl ring in any position via a cyclohexyl ring carbon atom and may thereby form the cis- or the trans-stereoisomer of a compound according to the invention.
In a preferred embodiment, L is attached to the 4-position of the cyclohexyl ring
L is attached to the 3-position of the cyclohexyl ring
in all their stereoisomeric forms.
In an especially preferred embodiment, L is attached to the 4-position of the cyclohexyl ring.
Preferably, L is O-methylene, O-ethylene or O. More preferably, L is O-methylene, O- ethylene or most preferred O attached to the 4-position of the cyclohexyl ring.
Most preferably, L is O.
In preferred embodiments of the present invention one or more or all of the groups contained in the compounds of formulae (I) or (I1) can independently of each other have any of the preferred, more preferred or most preferred definitions of the groups specified above or any one or some of the specific denotations which are comprised by the definitions of the groups and specified above, all combinations of preferred definitions, more preferred or most preferred and/or specific denotations being a subject of the present invention. Also with respect to all preferred embodiments the invention includes the compounds of the formulae (I) or (I') in all stereoisomeric forms and mixtures of stereoisomeric forms in all ratios, and/or their physiologically acceptable salts.
A preferred embodiment of the present invention is a compound of the formulae (I), (I1), (II) or (II1) wherein
R3 is H, halogen, CN, (C1-C6)alkyl, (Ci-C6)alkylene-R', OH, O-R", NH2, or NHR"; R4 is H, halogen, hydroxy, CN, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C1-C6)alkylene-R1;
R5 is H, halogen, CN, NO2, (C1-C6)alkyl, (C2-C6)alkenyl, R1, (C 1 -C6)alkylene-(C6-C 1 o)aryl, (C2-C6)alkenylene-(C6-C -| 0)aryl, (C1-C6)alkylene-(C5-C«|o)heterocyclyl, NH2, NH-R', NH-SO2H, NH-SO2-(C1-C6)alkyl, NH-SO2-R', NH-C(O)-(C1 -C6)alkyl, NH-C(O)-R', C(O)N[(C1-C6)alkyl]2, C(O)OH or C(O)O-(C<\-CQ)a\ky\;
RQ and RQ are independently of each other H, (C3-C8)cycloalkyi, (Ci-C8)alkyl, (C-i-C6)alkylene-R', (Ci-C6)alkylene-O-(C«|-C6)alkyl, (C1-C6)alkylene-O-R1,
(C1-C6)alkylene-CH[R']2, (Ci-C6)alkylene-C(O)NH2, (C1-C6)alkylene-C(O)NH-R'I or (Ci-C6)alkylene-C(O)N[R']2;
R7 and Rs are independently of each other H, halogen, CN, NO2, (C-|-C6)alkyl, (C2-C6)alkenyl, R', (C2-C6)alkenylene-(C6-Cio)aryl, (C-|-C6)alkylene-R', NH2, NH-R', NH-SO2-(C1-C6)alkyl, NH-SO2-R', SO2-NH2, SO2-NHR', NH-C(O)-(C-|-C6)alkyl, NH- C(O)-R', C(O)NJ(C1 -C6)alkyl]2, C(O)OH or C(O)O-(C <|-C6)alkyl;
Rg is halogen or (C-i-CβJalkyl; n is O, 1 , 2; and
L is O or 0-(C^-C2)a\^γ\ene;
wherein R1 , R2, R', R", Rx and Ry are as defined above;
or their pharmaceutically acceptable salts and/or stereoisomer^ forms and/or physiologically functional derivatives.
A further preferred embodiment of the present invention is a compound of the formulae (I), (I1), (II) or (II1) wherein R3 is H, halogen, CN, (CyCQ)a\ky\, (C-i-C66)alkylene-R1 or NHR";
R4 is H, halogen, CN1 (C-i-C^alkyl, (C3-C8)cycloalkyl, (C-i-C6)alkylene-R1;
R5 is H, halogen, CN, NO2, (C-i-C^alkyl, (C2-C6)alkenyl, R', (C1-C6)alkylene-CC6-CioJaryl. ^-C6)alkenylene^C6-CToJaryl, (C1-C6)alkylene-(C5-Cio)heterocyclyl, NH2, NH-R', NH-C(O)-(C1 -CβJalkyl, or CζOJNKC-i-CβJalkylfe;
Rβ and RQ' are independently of each other H, (C3-C8)cycloalkyl, (C-|-C8)alkyl, or (C-|-C3)alkylene-R';
R7 and Rg are independently of each other H, halogen, CN, NO2, (C-i-CβJalkyl, (C2-C6)alkenyl, R', (C2-C3)alkenylene-(C6-C10)aryl, (Ci-C3)alkylene-R', NH-R', NH- SO2-(C1 -C6)alkyl, or SO2-NH2;
Rg is halogen or (C-i-CβJalkyl;
n is O or 1 ; and
L is O or O-methylene;
wherein R1 , R2, R', R", Rx and Ry are as defined above;
or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.
A most preferred embodiment of the present invention is a compound of the formulae (I), (I1), (II) or (II1) wherein R3 is H, halogen, CN, (C1-C6)alkyl, (C<|-C2)alkylene-R' or NHR";
R4 is H, halogen, CN, (C-i-C6)alkyl, (C3-C6)cycloalkyl, (C-|-C2)alkylene-R';
R5 is H, halogen, CN, NO2, (C«|-C6)alkyl, (C2-C6)alkenyl, R', (C1-C6)alkylene-CC6-CioJaryl, (C2-C6)alkenylene-(C6-Cio)aryl, (C-] -C6)alkylene-(C5-Ci o)heterocyclyl, NH-R';
RQ is H, (C3-C6)cycloalkyl or (C<|-C4)alkyl;
Rβ' is H, (C3-C8)cycloalkyl, (C<|-C8)alkyl, or (C<|-C3)alkylene-R';
R7 and Re are independently of each other H, halogen, CN, NO2, (C-|-C6)alkyl, (C2-Cg)alkenyl, R', (C2-C3)alkenylene-(C6-C-jo)aryl. (Ci-C3)alkylene-R', NH-SO2-(Ci-C6)alkyl, or SO2-NH2;
Rg is halogen or (C-j-C6)alkyl;
n is 0 ; and L is O;
wherein R<| , R2, R', R", Rx and Ry are as defined above;
or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.
In another most preferred embodiment of the present invention is a compound of the formulae (I), (I1), (II) or (II1) wherein
R3 is H, halogen, (C<|-C6)alkyl; F*4 is H, halogen, (Ci-C4)alkyl;
R5 is H1 halogen, (C-|-C6)alkyl;
RQ is H, (C3-C8)cycloalkyl, or (Ci-Cs)alkyl;
R6 1 is H, (C3-C8)cycloalkyl, (C-i-CgJalkyl, or (Ci-C3)alkylene-R';
R7 and Re are independently of each other H, halogen, CN, (Ci-Cβjalkyl or SO2-NH2;
Rg is halogen or (C<|-C4)alkyl;
n is 0 ; and
L is O;
wherein R-| , R2, and R' are as defined above;
or their pharmaceutically acceptable salts and/or stereoisomer^ forms and/or physiologically functional derivatives.
As in any embodiment of the invention, in the preceding embodiments which contain preferred, more preferred, most preferred or exemplary definitions of compounds according to the invention, one or more or all of the groups can have any of its preferred, more preferred, most preferred definitions specified above or any one or some of the specific denotations which are comprised by its definitions and are specified above.
Physiologically acceptable salts of compounds of the formulae (I) and (I1) mean both their organic and inorganic salts as described in Remington's Pharmaceutical Sciences (17th edition, page 1418 (1985)). Because of the physical and chemical stability and the solubility, preference is given for acidic groups inter alia to sodium, potassium, calcium and ammonium salts; preference is given for basic groups inter alia to salts of maleic acid, fumaric acid, succinic acid, malic acid, tartaric acid, methylsulfonic acid, hydrochloric acid, sulfuric acid, phosphoric acid or of carboxylic acids or sulfonic acids, for example as hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, acetates, lactates, maleates, fumarates, malates, gluconates, and salts of amino acids, of natural bases or carboxylic acids. The preparation of physiologically acceptable salts from compounds of the formulae (I) and (I1) which are capable of salt formation, including their stereoisomeric forms, takes place in a manner known per se. The compounds of the formula (I) form stable alkali metal, alkaline earth metal or optionally substituted ammonium salts with basic reagents such as hydroxides, carbonates, bicarbonates, alcoholates and ammonia or organic bases, for example trimethyl- or triethylamine, ethanolamine, diethanolamine or triethanolamine, trometamol or else basic amino acids, for example lysine, ornithine or arginine. Where the compounds of the formulae (I) or (I1) have basic groups, stable acid addition salts can also be prepared with strong acids. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acid, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acid.
Salts with a physiologically unacceptable anion such as, for example, trifluoroacetate likewise belong within the framework of the invention as useful intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.
The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound of the formulae (I) or (I1) of the invention, for example an N-oxide, which on administration to a mammal such as, for example, a human is able to form (directly or indirectly) a compound of the formula (I) or (I') or an active metabolite thereof.
Physiologically functional derivatives include prodrugs of the compounds of the invention, as described, for example, in H. Okada et al., Chem. Pharm. Bull. 1994, 42, 57-61. Such prodrugs can be metabolized in vivo to a compound of the invention. These prodrugs may themselves be active or not.
The invention relates to a compound of the formula (I) or (I1) in the form of their racemates, racemic mixtures and pure enantiomers and to their diastereomers and mixtures thereof.
If radicals or substituents may occur more than once in the compounds of the formulae (I) or (I1), they may all, independently of one another, have the stated meaning and be identical or different.
The compounds of the invention may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the invention belong within the framework of the invention and are a further aspect of the invention.
All references to "compound(s) of formula (I)" or to "compound(s) of formula (I1)" hereinafter refer to compound(s) of the formulae (I) or (I') as described above, and their physiologically acceptable salts, solvates and physiologically functional derivatives as described herein.
The term alkyl and the corresposponding alkylene substituents are understood as a hydrocarbon residue which can be linear, i.e. straight-chain, or branched and has 1 , 2, 3, 4, 5 or 6 carbon atoms, respectively, where applicable. This also applies if an alkyl group occurs as a substituent on another group, for example in an alkoxy group
(O-alkyl), S-alkyl or a -O(C*|-C6)alkylene-O-, an alkoxycarbonyl group or an arylalkyl group. Examples of alkyl groups are methyl, ethyl, propyl, butyl, pentyl or hexyl, the n- isomers of all these groups, isopropyl, isobutyl, 1-methylbutyl, isopentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, isohexyl, sec-butyl, tert-butyl or tert- pentyl. Alkyl groups may - if not otherwise stated - be halogenated once or more, e.g. alkyl groups may be fluorinated, e.g. perfluorinated. Examples of halogenated alkyl groups are CF3 and CH2CF3, OCF3, SCFβ, or -O-(CF2)2-O-.
Alkenyl are, for example, vinyl, 1-propenyl, 2-propenyl (= allyl), 2-butenyl, 3-butenyl, 2- methyl-2-butenyl, 3-methyl-2-butenyl, 5-hexenyl or 1,3-pentadienyl.
Alkynyl are, for example, ethynyl, 1-propynyl, 2-propynyl (= propargyl) or 2-butynyl.
Halogen means fluoro, chloro, bromo or iodo.
(C3-C8)cycloalkyl groups are cyclic alkyl groups containing 3, 4, 5, 6, 7 or 8 ring carbon atoms like cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl, which can also be substituted and/or contain 1 or 2 double bonds (unsaturated cycloalkyl groups) like, for example, cyclopentenyl or cyclohexenyl can be bound via any carbon atom.
A (C5-C-|o)aryl group means an aromatic ring or a ring system which comprises two aromatic rings which are fused or otherwise linked, for example a phenyl, naphthyl, biphenyl, tetrahydronaphthyl, alpha- or beta-tetralon-, indanyl- or indan-1-on-yl group. A preferred (Cg-C10)aryl group is phenyl.
A (C5-Cio)neterocyclyl group means a mono- or bicyclic ring system which comprises, apart from carbon, one or more heteroatoms such as, for example, e.g. 1 , 2 or 3 nitrogen atoms, 1 or 2 oxygen atoms, 1 or 2 sulfur atoms or combinations of different hetero atoms. The heterocyclyl residues can be bound at any positions, for example on the 1 -position, 2-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8- position. (C5-C<|o)neterocyc|y| groups may be (1) aromatic [= heteroaryl groups] or (2) saturated or (3) mixed aromatic/saturated. Suitable (C5-Cio)heterocyclyl groups include acridinyl, azocinyl, benzimidazolyl, benzofuryl, benzomorpholinyl, benzothienyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, carbazolyl, 4aH-carbazolyl, carbolinyl, furanyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl, chromen-2-onyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furazanyl, homomorpholinyl, homopiperazinyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1 ,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, prolinyl, pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridonyl, pyridooxazoles, pyridoimidazoles, pyridothiazoles, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1 ,2,5-thiadazinyl, thiazolyl, 1,2,3- thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthenyl. Pyridyl stands both for 2-, 3- and 4-pyridyl. Thienyl stands both for 2- and 3-thienyl. Furyl stands both for 2- and 3-furyl. Also included are the corresponding N-oxides of these compounds, for example, 1-oxy-2-, 3- or 4-pyridyl.
Substitutions in (C5-Cio)heterocyclyl residues can occur on free carbon atoms or on nitrogen atoms.
Preferred examples of (C5-Cio)heterocyclyl residues are pyrazinyl, pyridyl, pyrimidinyl, pyrazolyl, morpholinyl, pyrrolidinyl, piperazinyl, piperidinyl, thienyl, benzofuryl, quinolinyl, tetrazolyl and triazolyl.
(Cβ-C-i o)aryl and (C5-Cirj)neterocyclyl groups are unsubstituted or, if not otherwise stated, substituted one or more times by suitable groups independently selected from halogen, CF3, NO2, N3, CN1 C(O)-(C1-C6)alkyl. C(O)-(Ci -Cβjaryl, COOH, COO(Ci- C6)alkyl, CONH2, CONH(C1-C6)alkyl, CON[(C1-C6)alkyl]2, (C3-C8)cycloalkyl, (C1-C6)alkyl, (C1-C6)alkylene-OH, (C1-C6)alkylene-NH2, (C1-C6)alkylene-NH(C1- C6)alkyl, (C1-C6)alkylene-N[(C1-C6)alkyl]2, (C2-C6)alkenyl, (C2-C6)alkynyl, O- (C1-C6)alkyl, 0-C(O)-(C1-C6)alkyl, 0-C(O)-(C6-C10)aryl, 0-C(O)-(C5-C1 o)heterocyclyl, PO3H2, SO3H, SO2-NH2, SO2NH(C1-C6)alkyl, SO2N[(C1-C6)alkyl]2 , S-(C1-C6)alkyl; S-(C1-C6)alkylene-(C6-C10)aryl, S-(C1-C6)alkylene-(C5-C10)heterocyclyl, SO-(C1-C6)alkyl,
SO-(C1-C6)alkylene-(C6-C10)aryl, SO-(C1-C6)alkylene-(C5-C10)heterocyclyl, SO2- (C1-C6)alkyl, SO2-(C1-C6)alkylene-(C6-C10)aryl, SO-(C1--C6)alkylene-(C5-C10)heterocyclyl, SO2-NH(C1-C6)alkylene-(C6-C10)aryl, SO2-NH-(C1-C6)alkylene-(C5-C10)heterocyclyl. SO2-[(C1-C6) alkyl][(C1-C6)alkylene- (C6-C10)aryl], SO2-N[(C1-C6)alkyl ][(C1-C6)alkylene-(C5-C10)heterocyclyl],
SO2-N[(C1-C6)alkylene-(C6-C10)aryyl]2, SO2-N[(C1-C6)alkylene-(C5-C10)heterocyclyl]2, C(NH)(NH2), NH2, NH-(C 1-C6)alkyl, N[(C1-C6)alkyl]2, NH-C(O)-(C1 -C6)alkyl,
NH-C(O)O-(C1-C6)alkyl, NH-C(O)-(C6-C10)aryl, NH-C(O)-(Cs-C10)heterocyclyl, NH- C(O)O-(C6-C10)aryl, NH-C(O)O-(C5-C10)heterocyclyl, NH-C(O)-NH-(C1-C6)alkyl, NH- C(O)-NH-(C6-C10)aryl, NH-C(O)-NH-(C5-C10)heterocyclyl, NH-SO^C1-C6)alkyl, NH-SO2-(C6-C10)aryI, NH-SO2-(C5-C10)heterocyclyl, N(C1-C6)alkyl-C(O)- (C1-C6)alkyl, N(C1-C6)alkyl-C(O)O-(C1-C6)alkyl, N(C1-C6)alkyl-C(O)-(C6-C10)aryl, N^-i-C6)alkyl-C(O)-heterocyclyl, N(C1-C6)alkyl-C(O)O-(C6-C10)aryl, N(C1-C6)alkyl- C(O)O-(C5-C10)heterocyclyl, (C1-C6 )alkyl-C(O)-NH^C-i-C6)alkyl], N(C1-C6)alkyl- C(O)-N H-(C6-C10)aryl, N(C1-C6)alkyl-C(O)-NH-(C5-C10)heterocyclyl, N[(C1-C6)alkyll-C(O)-N[(C1-C6)alkyl]2, N[(C1-C6)alkyll-C(O)-N[(C1-C6)alkylHC6-C10)aryl,
N[(C1-C6)alkyl]-C(O)-N[(C1-C6)alkyl]-(C5-C10)heterocyclyl, N[(C1-C6)alkyl]-C(O)-N[(C6-C10)aryl]2, N[(C1-C6)alkyl]-C(O)-N[(C5-C10)heterocyclyl]2, N[(C6-C10)aryl]-C(O)-(C1-C6)alkyl, N[(C5-C10)heterocyclyl]-C(O)-(C1-C6)alkyl) N[(C6-C10)aryl]-C(0)0-(C1-C6)alkyl, N[(C5-C10)heterocyclyl]-C(0)0-(C1-C6)alkyl, NCaFyI)-C(O)-(C6-C1 o)aryl, Nl(C5-C10)heterocyclyl]-C(O)-(C6-C10)aryl, NI(C6-C1 Q)BrYl]-C(O)O-(C6-C10)aryl, N[(C5-C10)heterc)cyclyl]-C(0)0-(C6-C10)aryll N[(C6-C10)aryl]-C(0)-NH-(C1-C6)alkyl, N[(C5-C10)heterocyclyl]-C(O)-NH-(C1-C6)alkyl, N(aryl)-C(O)-NH-(C6-C10)aryl, N[(C5-C10)JIeIeFOCyCIyI]-C(O)-NH-(C6-C1 o)aryl, NKC6-C^Jaryll-C^J-N[(C1-C6)alkylla,
N[(C5-C10)heterocyclyl]-C(O)-N[(C1-C6)alkyl]2, Nf(C6-C 10)aryl]-C(O)-N[(C1-C6)alkyl]- (C6-C10)aryl. NKCδ-C^Jheterocyclyll-C(O)-N[(C1-C6)alkylKC6-C10)aryl, NKC6-C10)BrYl]-C(O)-NI(C6-C1 o)aryl]2,
N[(C5-C10)heterocyclyl]-C(0)-N[(C6-C10)aryl]2, (C6-C10)aryl, (C1-C6)alkylene^C6-C10)aryl, O-(C1-C6)alkylene-(C6-C10)aryl, (C5-C10)heterocyclyl, (C1-C6)alkylene^Cs-C^heterocyclyl, O-(C1-C6)alkylene-ζCs-C^heterocyclyl, wherein the (C6-C1 o)aryl or (C5-C1 o)heterocyclyl may be substituted one to 3 times by halogen, OH, NO2, CN, O-(C1-C6)alkyl, (C1-C6JaIkYl, NH2, NH^-i-C6)alkyl,
NI(C1 -C6)alkyl]2, SO2CH3, COOH, C(O)O-(C1-C6JaIkYl, CONH2, (C1-C6)alkylene-O- (C-|-C6)alkyl, (C1-C6)alkylene-O-^e-C-ioiaryl, O-tC-i-C6)alkylene^C6-C^aryl; or wherein (C6-C1 o)aryl is vicinally substituted by a O-tC-i-C6)alkylene-O group whereby a 5-8-membered ring is formed together with the carbon atoms the oxygen atoms are attached to. Aryl or heterocyclyl substituents of (C6-C1 o)aryl and (C5-C1 o)heterocyclyl groups may not be further substituted by an aryl or heterocyclyl containing group.
If substituted, preferred substituents for (C6-C10)aryl groups are (C-|-C4)alkyl, 0-(C1- C4)alkyl, O-phenyl, C(O)O-(C1 -C6)alkyl, C(O)OH, C(O)-(C1-C6)aIkYl, halogen, NO2, SO2NH2, CN, SO2-(C1 -C4)alkyl, NH-SO2-(C1-C6)aIlCyI1 NH2, NH-CfOHC-i-C6)alkyl, (C3-C8)cycloalkyl, (C1-C4)aIkYl-OH, C(O)NI(C1 -C4)alkyl]2, C(O)NH2, NI(C1- C4)alkyl]2, (C1-C6)alkenylene-^e-C^Jaryl, wherein the (C6-C«ιo)aryl may be further substituted by (C1-C4JaIkYl, (C-i-C6)alkylene-O^C-i-C6)alkyl, O^C-i-C6)alkyl-^e-C10)aryl, or may be vicinally substituted by a O-tC-i-C6)alkylene- O group whereby a 5-8-membered ring is formed together with the carbon atoms the oxygen atoms are attached to. More preferred substituents for (C<|-C6)alkylene-(C6- C-|o)aryl are halogen, (C-|-C4)alkyl especially CH3 or CF3, O-(Ci-C4)alkyl especially 0-CHa1 or SO2-(C-|-C4)alkyl especially SO2-CH3 or SO2-CF3.
In monosubstituted phenyl groups the substituent can be located in the 2-position, the 3-position or the 4-position, with the 3-position and the 4-position being preferred. If a phenyl group carries two substituents, they can be located in 2, 3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In phenyl groups carrying three substituents the substituents can be located in 2,3,4-position, 2,3,5-position, 2,3,6- position, 2,4,5-position, 2,4,6-position, or 3,4,5-position.
The above statements relating to phenyl groups correspondingly apply to divalent groups derived from phenyl groups, i.e. phenylene which can be unsubstituted or substituted 1 ,2-phenylene, 1 ,3-phenylene or 1 ,4-phenylene. The above statements also correspondingly apply to the aryl subgroup in arylalkylene groups. Examples of arylalkylene groups which can also be unsubstituted or substituted in the aryl subgroup as well as in the alkylene subgroup, are benzyl, 1-phenylethylene, 2-phenylethylene, 3- phenylpropylene, 4-phenylbutylene, 1-methyl-3-phenyl-propylene.
If substituted, preferred substituents for (C5-C-jn)heterocyclyl groups are (C-|-C4)alkyl,
O-(C-|-C4)alkyl, (C-|-C4)alkylene-phenyl, halogen, (C-|-C4)alkylene-O-(C-|-C4)alkyl, (C5-C<|o)heterocyclyl, (C-|-C4)alkylene-N[(C-|-C4)alkyl]2, or (Cg-Ci n)aryl, wherein the (Cβ-CioOaryl may De further substituted by (Ci-C^alkyl, (C-|-C4)alkylene-O-(C1-C6)alkyl, O-(C1-C6)alkyl-(C6-Cirj)aryl, or may be vicinally substituted by a O-(Ci -Chalky lene-O group whereby a 5-8-membered ring is formed together with the carbon atoms the oxygen atoms are attached to. More preferred substituents for (C5-C<jrj)heterocyclyl groups are (C<|-C4)alkyl or halogen. The general and preferred substituents of (C6-C-|o)aryl ar|d (C5-C<|rj)heterocyclyl groups may be combined with the general and preferred definitions of R^ , R2, R3, R4, R5. Rβ> Rβ' > R7- Rδ- R9» n and L as described above.
The present invention therefore also relates to the compounds of the formulae (I) or (I1) and/or their physiologically acceptable salts and/or stereoisomer^ forms for use as pharmaceuticals (or medicaments), to the use of the compounds of the formulae (I) or (I1) and/or their physiologically acceptable salts and/or stereoisomeric forms for the production of pharmaceuticals for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, i.e. for the treatment and/or prevention of hypertension, pulmonary hypertension, ocular hypertension, retinopathy, and glaucoma, peripheral circulatory disorder, peripheral occlusive arterial disease (PAOD), coronary heart disease, angina pectoris, heart hypertrophy, heart failure, ischemic diseases, ischemic organ failure (end organ damage), fibroid lung, fibroid liver, liver failure, nephropathy, including hypertension-induced, non-hypertension-induced, and diabetic nephropathies, renal failure, fibroid kidney, renal glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, e.g. neuropathic pain, neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes and complications of diabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy such as osteoporosis, infection of digestive tracts with bacteria, sepsis, cancer development and progression, e.g. cancers of the breast, colon, prostate, ovaries, brain and lung and their metastases.
The treatment and/or prevention of diseases in humans is a preferred embodiment but also warm blooded animals such as cats, dogs, rats, horses etc. may be treated with the compounds of the present invention. The present invention furthermore relates to pharmaceutical preparations (or pharmaceutical compositions) which contain an effective amount of at least one compound of the formula (I) or (I1) and/or its physiologically acceptable salts and/or stereoisomeric forms and a pharmaceutically acceptable carrier, i. e. one or more pharmaceutically acceptable carrier substances (or vehicles) and/or additives (or excipients).
Optionally the physiologically functional derivatives, including the prodrugs, of a compound of the formula (I) or (I') may be utilized in the above mentioned uses and pharmaceutical preparations.
The pharmaceuticals can be administered orally, for example in the form of pills, tablets, lacquered tablets, coated tablets, granules, hard and soft gelatin capsules, solutions, syrups, emulsions, suspensions or aerosol mixtures. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injection solutions or infusion solutions, microcapsules, implants or rods, or percutaneously or topically, for example in the form of ointments, solutions or tinctures, or in other ways, for example in the form of aerosols or nasal sprays.
The pharmaceutical preparations according to the invention are prepared in a manner known per se and familiar to one skilled in the art, pharmaceutically acceptable inert inorganic and/or organic carrier substances and/or additives being used in addition to the compound(s) of the formulae (I) or (I1) and/or its (their) physiologically acceptable salts and/or its (their) stereisomeric forms as well as its (their) prodrugs. For the production of pills, tablets, coated tablets and hard gelatin capsules it is possible to use, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts, etc. Carrier substances for soft gelatin capsules and suppositories are, for example, fats, waxes, semisolid and liquid polyols, natural or hardened oils, etc. Suitable carrier substances for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, saline, alcohols, glycerol, polyols, sucrose, invert sugar, glucose, vegetable oils, etc. Suitable carrier substances for microcapsules, implants or rods are, for example, copolymers of glycolic acid and lactic acid. The pharmaceutical preparations normally contain about 0.5 to about 90 % by weight of a compound of the formula (I) or (I1) and/or their physiologically acceptable salts and/or their stereisomeric forms. The amount of the active ingredient of the formula (I) or (I1) and/or its physiologically acceptable salts and/or its stereisomeric forms in the pharmaceutical preparations normally is from about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg.
In addition to the active ingredients of the formula (I) or (I1) and/or their physiologically acceptable salts and/or stereisomeric forms and to carrier substances, the pharmaceutical preparations can contain one or more additives such as, for example, fillers, disintegrants, binders, lubricants, wetting agents, stabilizers, emulsifiers, preservatives, sweeteners, colorants, flavorings, aromatizers, thickeners, diluents, buffer substances, solvents, solubilizers, agents for achieving a depot effect, salts for altering the osmotic pressure, coating agents or antioxidants. They can also contain two or more compounds of the formulae (I) and/or (I1) and/or their physiologically acceptable salts and/or their prodrugs. In case a pharmaceutical preparation contains two or more compounds of the formulae (I) and/or (I1), the selection of the individual compounds can aim at a specific overall pharmacological profile of the pharmaceutical preparation. For example, a highly potent compound with a shorter duration of action may be combined with a long-acting compound of lower potency. The flexibility permitted with respect to the choice of substituents in the compounds of the formulae (I) or (I1) allows a great deal of control over the biological and physico-chemical properties of the compounds and thus allows the selection of such desired compounds. Furthermore, in addition to at least one compound of the formula (I) or (I1) and/or its physiologically acceptable salts and/or its stereisomeric forms, the pharmaceutical preparations can also contain one or more other therapeutically or prophylactically active ingredients.
When using the compounds of the formulae (I) or (I1) the dose can vary within wide limits and, as is customary and is known to the physician, is to be suited to the individual conditions in each individual case. It depends, for example, on the specific compound employed, on the nature and severity of the disease to be treated, on the mode and the schedule of administration, or on whether an acute or chronic condition is treated or whether prophylaxis is carried out. An appropriate dosage can be established using clinical approaches well known in the medical art. In general, the daily dose for achieving the desired results in an adult weighing about 75 kg is from about 0.01 to about 100 mg/kg, preferably from about 0.1 to about 50 mg/kg, in particular from about 0.1 to about 10 mg/kg, (in each case in mg per kg of body weight). The daily dose can be divided, in particular in the case of the administration of relatively large amounts, into several, for example 2, 3 or 4, part administrations. As usual, depending on individual behavior it may be necessary to deviate upwards or downwards from the daily dose indicated.
Furthermore, the compounds of the formulae (I) or (I1) can be used as synthesis intermediates for the preparation of other compounds, in particular of other pharmaceutical active ingredients, which are obtainable from the compounds of the formula I, for example by introduction of substituents or modification of functional groups.
It is understood that modifications that do not substantially affect the activity of the various embodiments of this invention are included within the invention disclosed herein.
The compounds of the formulae (I) or (I') can be prepared according to the following exemplified compounds without limiting the scope of the claims.
In general, protective groups that may still be present in the products obtained in the coupling reaction are then removed by standard procedures. For example, tert-butyl protecting groups, in particular a tert-butoxycarbonyl group which is a protection form of an amino group, can be deprotected, i. e. converted into the amino group, by treatment with trifluoroacetic acid. As already explained, after the coupling reaction also functional groups can be generated from suitable precursor groups. In addition, a conversion into a physiologically acceptable salt or a prodrug of a compound of the formulae (I) or (I1) can then be carried out by known processes.
In general, a reaction mixture containing a final compound of the formula (I) or (I1) or an intermediate is worked up and, if desired, the product is then purified by customary processes known to those skilled in the art. For example, a synthesized compound can be purified using well known methods such as crystallization, chromatography or reverse phase-high performance liquid chromatography (RP-HPLC) or other methods of separation based, for example, on the size, charge or hydrophobicity of the compound. Similarly, well known methods such as amino acid sequence analysis, NMR, IR and mass spectrometry (MS) can be used for characterizing a compound of the invention.
Isoquinolinones can by synthesized via a variety of methods. The following general schemes illustrate some of the possible ways to access isoquinolones, but do not limit the present invention.
Scheme 1 : A suitably substituted aldehyde, for example substituted by X or Y being independently from each other hydrogen, alkyl, alkoxy or halide attached in a suitable position, can be reacted with a suitable compound such as for example an actal of aminoacetaldehyde for example in a solvent like THF, chloroform or toluene under acid catalysis by toluene sulfonic acid or another appropriate acid to give imine (ii) wherein Q' can be for instance methyl or ethyl, which in turn can be cyclized by different methods to the isoquinoline (iii). For example this can be done by Lewis acid catalysis by suitable Lewis acids like titanium tetrachloride, ferrous halides, aluminium halides etc. at temperatures ranging from ambient to 100 0C or by reducing the imine to the corresponding amine by action of a suitable reducing agent like sodium borohydride, converting the amine into an amide or sulphonamide by reaction with a suitable acid chloride and subsequent cyclization to the isoquinoline by action of an appropriate lewis acid. The isoquinoline (iii) itself can then be converted to the corresponding N- oxide (iv) by action of a suitable oxidative agent like hydrogen peroxide, m-chloro perbenzoic acid or others at room temperature or elevated temperature. The N-oxide (iv) can then be converted into the 1-chloro-isoquinoline derivative (v) by reacting it with a reagent like phosphorous oxy chloride in or without presence of phosphorous pentachloride. The derivative (v) can then be turned into suitable 1 -alkoxy-derivatives by reacting it with various alcohols Q-OH like methanol, ethanol or benzyl alcohol in the presence of a suitable base like sodium hydride and in a suitable solvent like dimethyl formamide, dimethyl acetamide or others. Alternatively (v) can be directly converted into the isoquinolinone derivative (vii) by reacting it with a reagent like ammonium acetate.
Scheme 2
Alternatively isoquinolines can be obtained by reacting suitable 3-formylated or acylated fluorobenzenes (viii), wherein z is for example H or alkyl like methyl or ethyl, with a reagent like triethyl phosphono acetate in the presence of a suitable base like sodium hydride to give the corresponding cinnamic acid ester, which subsequently is cleaved by action of a suitable base like potassium hydroxide, sodium hydroxide or lithium hydroxide in a suitable solvent to deliver acid (ix). (ix) can then be converted in the corresponding acid chloride by well known methods, which can be transferred into the acid azide by reaction with sodium azide in a suitable solvent like ether, chloroform or acetone in or without the presence of water. The corresponding azide then can be converted into isoquinolinone (x) by reacting it in a suitable solvent like diphenylmethane or dipenylether at suitable temperature.
(xiii)
Scheme 3:
The above obtained 6-Fluoro-isoquinolones, for example (vi), can be reacted with suitable Pi / P2 substituted amino alcohols wherein Pi / P2 are independently from each other for example hydrogen, alkyl or a protecting group like for example Boc or phthaloyl in the presence of base such as DBU, cesium carbonate or sodium hydride to give the corresponding alkoxy substituted derivatives (xi). Eventually, this conversion can already by performed at earlier stages of the synthesis (e.g. by reacting a suitable intermediate). It is understood, that this may require in case of unprotected isoquinolones protection on the nitrogen or oxygen of the isoquinolone moiety by suitable methods, like reaction with suitably substituted alkyl or benzyl halides in the presence of base. The products like (xi) obtained via this method can then either be liberated or, if a suitable amino functionality is present, be reacted with suitable aldehydes or ketones in the presence of a reducing agent like sodium triacetoxy borohydride, sodium borohydride or sodium cyanoborohydride in a suitable solvent and in the presence of a water withdrawing agent like molecular sieves or a suitable ortho ester. This amino group may have to be liberated in an initial step like for example acidic removal of Boc- groups.
In case of use of protected isoquinolones, cleavage of the used protection groups is required to liberate the desired isoquinolone (xii). This liberation, however, can be performed before or after the reductive amination step, depending on the nature of the used aldehyde / ketone and the protection group used.
Isoquinolone derivatives like (xii) can be obtained as free bases or as various salts like for example hydrochlorides, hydrobromides, phosphates, trifluoroacetates, sulfates or fumarates. The salts obtained can be converted into the corresponding free base by either subjecting them to ion exchange chromatography or for example by alkaline aqueous treatment and subsequent extraction with suitable organic solvents like for example methyl tert. butyl ether, chloroform, ethyl acetate or isopropanol / dichloromethane mixtures and subsequent evaporation to dryness.
The general methods for the preparation of isoquinolone derivatives as described above can be readily adapted to the preparation of the compounds of the formula (I) or (r). In the following examples the preparation of the compounds of the present invention is outlined in more detail. Accordingly, the following examples are part of and intended to illustrate but not to limit the present invention.
(2,2-Dimethoxy-ethyl)-(4-fluoro-benzyl)-amine (1)
12.4 g of 4-fIuorobenzaldehyde were dissolved in 100 ml_ of toluene and reacted with
10.5 g of 2-aminoacetaldehyde dimethylacetal and 1.90 of p-toluenesulfonic acid monohydrate for two hours at a Dean Stark apparatus. The solution was allowed to cool down, extracted with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated to dryness. The crude product was dissolved in 100 ml_ of ethanol. 1.89 g of sodium borohydride were added portionwise. Stirring was continued overnight. For workup, acetic acid was added until no gas evolution could be observed. Then the solution was evaporated to dryness, taken up in dichloromethane and washed twice with water. The organic layer was extracted with brine, dried over magnesium sulfate and evaporated to dryness. The obtained crude product (20 g) was used for further reactions without purification. Rt = 0.86 min (Method B). Detected mass: 182.1 (M-OMe ), 214.2 (M+H+).
N-(2,2-Dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl-benzene-sulfonamide (2)
20 g of (2,2-dimethoxy-ethyl)-(4-fluoro-benzyl)-amine (1) were dissolved in 120 ml of dichloromethane. 20 mL of pyridine were added. At 0 0C a solution of 23.8 g p- toluenesulfonic acid chloride in dichloromethane was added dropwise. The reaction was allowed to warm to room temperature and stirring is continued until conversion was completed. For workup, the reaction mixture was extracted twice with 2M hydrochloric acid, twice with sodium bicarbonate and once with brine. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product was purified by silica gel chromatography to yield 22.95 g of compound 2 as an orange oil. Rt = 1.71 min (Method C). Detected mass: 336.1 (M-OMe'). 6-Fluoro-isoquinoline (3)
41.6 g Of AICI3 were suspended in 400 ml_ of dichloromethane. At room temperature, a solution of 22.95 g of N-(2,2-dimethoxy-ethyl)-N-(4-fluoro-benzyl)-4-methyl- benzenesulfonamide (2) in 150 ml of dichloromethane was added. Stirring was continued at room temperature overnight, the solution was poured on ice, the organic layer was separated, the aqueous phase was extracted twice with dichloromethane and the combined organic layers were then extracted twice with sodium bicarbonate. The organic layer was dried over magnesium sulfate, evaporated to dryness and the obtained crude product (8.75g) is purified by silica gel chromatography to yield 2.74 g of compound (23). Rt = 0.30 min (Method C). Detected mass: 148.1 (M+H+).
7-Chloro-6-fluoro-isoquinoline (4)
Starting from 3-chloro-4-fluoro-benzaldehyde, the title compound was prepared by the same reaction sequence as used for the synthesis of 6-fluoro-isoquinoline (3). Rt = 0.77 min (Method A). Detected mass: 182.1/184.1 (M+H+).
7-Bromo-6-fluoro-isoquinoline (92)
Starting from 3-bromo-4-fluoro-benzaldehyde, the title compound was prepared by the same reaction sequence as used for the synthesis of 6-fluoro-isoquinoline (3). Rt = 0.91 min (Method B). Detected mass: 226.0 / 228.0 (M+H+). 7-Chloro-6-fluoro-isoquinoline 2-oxide (5)
25 g (137.7 mmol) of 7-chloro-6-fluoro-isoquinoline (4) were in dissolved in 500 ml of dichloromethane. At room temperature 50.9 g (206.5 mmol) of m-chloro perbenzoic acid (70 %) were added and the mixture was stirred at room temperature until complete conversion is achieved. For workup, the precipitate was filtered off and washed with dichloromethane. The filtrate was washed twice with sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The organic phases were dried with magnesium sulfate and evaporated. The so obtained solid material (18.4 g) was used without further purification. R1 = 0.87 min (Method C). Detected mass: 198.1/200.1 (M+H+).
1 ,7-Dichloro-6-fluoro-isoquinoline (6)
2.6 g (12.0 mmol) of 7-chloro-6-fluoro-isoquinoline 2-oxide (5) were heated in 40 ml of POCI3 at reflux for 4 h. After the mixture has cooled down to room temperature, it was poured on ice. The aqueous solution was extracted three times with dichloromethane. The combined organic layers were dried with magnesium sulfate and evaporated to yield 2.91 g of the title compound, which was used without further purification. Rt = 2.34 min (Method A). Detected mass: 216.0/218.0 (M+H+).
5-Chloro-6-f1uoro-isoquinoline (7)
7.0 g (38.1 mmol) of 6-fluoroisoquinoline (3) were dissolved in 60 mL of concentrated sulfuric acid. At 0 0C 10.18 g of N-chloro succinimide were added. After 1 h another 5.2 g of N-chloro succiminide were added and the solution was heated to 50 0C. Two more portions of 5.2 g N-chloro succinimide were added successively and stirring was continued at 50 0C until the reaction was complete. The reaction mixture was cooled to room temperature, was poured on ice and adjusted to pH 10 by addition of sodium hydroxide. The precipitate was filtered off, dissolved in dichloromethane and washed with aqueous sodium hydroxide. The organic layer was dried over magnesium sulfate, evaporated and the crude product was purified by preparative HPLC to yield 4.04 g of 5-chloro-6-fluoro-isoquinoline (7) as trifluoroacetate. Rt = 0.97 min (Method A). Detected mass: 182.0/184.0 (M+H+).
5-Chloro-6-fluoro-isoquinoline 2 -oxide (8)
Starting from 5-chloro-6-fluoro-isoquinoline trifluoroacetate (7), the title compound was obtained following the method described for 7-chloro-6-fluoro-isoquinoline 2-oxide (5). Rt = 0.90 min (Method C). Detected mass: 198.1/200.1 (M+H+).
1 ,5-Dichloro-6-fluoro-isoquinoline (9)
5-Chloro-6-fluoro-isoquinoline 2-oxide (8) was converted to the title compound following the protocol described for the synthesis of 1 ,7-dichloro-6-fluoro-isoquinoline (6). The crude product was purified by silica gel chromatography (heptane/ethyl acetate 4:1). Rt = 1.70 min (Method C). Detected mass: 216.0/218.0 (M+H+).
6-(cis-4-Amino-cyclohexyloxy)-7-chloro-2H-isoquinolin-1 -one (10)
2.19 g (10.2 mmol) of c/s-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester were dissolved in 20 ml of dimethyl actetamide. Under argon atmosphere, 814 mg (20.4 mmol) of sodium hydride (60%) were added and the mixture was stirred at room temperature. After 30 min, a solution of 2.0 g (9.26 mmol) of 1 ,7-dichloro-6-fluoro- isoquinoline (6) in 5 ml of dimethyl acetamide was added and stirring was continued at room temperature. After 1 h, 2.0 g (18.5 mmol) of benzyl alcohol and 740 mg (18.5 mmol) of sodium hydride (60 %) were added. The reaction was stirred for 2 h at room temperature and 30 minutes at 80 0C to achieve complete conversion. The solvent was removed in vacuo and the residue was taken up in dichloromethane and washed twice with water. After drying over magnesium sulfate, the organic layer was evaporated, to furnish 4.44 g of the crude intermediate c/s-[4-(1-benzyloxy-7-chloro-isoquinolin-6- yloxy)-cyclohexyl]-carbamic acid tert-butyl ester. The intermediate was dissolved in methanol and treated with 2 N HCI at room temperature. After stirring for 2 d, the reaction mixture was adjusted to alkaline pH by addition of sodium hydroxide. The solvent was removed in vacuo and the residue was stirred in ethanol. Filtration and evaporation of the filtrate yielded a solid material, which was purified by preparative HPLC. The obtained trifluoroacetate was dissolved in 2 N HCI. Final lyophilization gave 433 mg of the title compound as hydrochloride. Rt = 0.89 min (Method B). Detected mass: 293.2/295.2 (M+H+).
6-(cis-4-Amino-cyclohexyloxy)-5-chloro-2H-isoquinolin-1-one (11)
Starting from c/s-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester and 1 ,5- dichloro-6-fluoro-isoquinoline (9), the title compound was prepared as hydrochloride following the route described for 6-(c/s-4-amino-cyclohexyloxy)-7-chloro-isoquinolin-1- ol hydrochloride (10). Rt = 1.04 min (Method B). Detected mass: 293.1/295.1 (M+H+). 7-Chloro-6-(cis-4-cyclopropylamino-cyclohexyloxy)-2H-isoquinolin-1 -one (12)
and
7-Chloro-6-(cis-4-dicyclopropylamino-cyclohexyloxy)-2H-isoquinolin-1-one (13)
100 mg (0.3 mmol) of 6-(cis-4-Amino-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one hydrochloride (10) were dissolved in 10 ml of methanol. 54.5 mg (0.54 mmol) of triethyl amine were added and the mixture was stirred at room temperature for 10 minutes. Freshly dried molecular sieves, 159.3 mg (2.66 mmol) of acetic acid, 104.6 mg (0.6 mmol) of (1-ethoxy-cyclopropoxy) trimethyl silane and 56.5 mg (0.9 mmol) of sodium cyanoborohydride were added and the reaction mixture was refluxed for 3 h. 5 equivalents of (i-ethoxy-cyclopropoxy)-trimethyl-silane were added, followed by 2 equivalents of sodium cyanoborohydride. The mixture was allowed to stand at room temperature overnight. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane, washed twice with 2 N NaOH and water and dried over magnesium sulfate. After evaporation of the solvent and purification by preparative HPLC 4.5 mg of 7-chloro-6-(c/s-4-cyclopropylamino-cyclohexyloxy)- isoquinolin-1-ol (12) as trifluoroacetate and 16 mg of 7-chloro-6-(c/s-4- dicyclopropylamino-cyclohexyloxy)-isoquinolin-1-ol (13) as trifluoroacetate were obtained. Rt (12) = 1.05 min (Method A). Detected mass: 333.2/335.2 (M+H+). Rt (13) = 1.15 min (Method B). Detected mass: 373.1/375.1 (M+H+). β-^raπs^-Amino-cyclohexyloxy^-chloro-isoquinolin-i-ol (14)
Starting from frans-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester and 1 ,7- dichloro-6-fluoro-isoquinoline (6) the title compound was prepared as hydrochloride following the route described for 6-(c/s-4-amino-cyclohexyloxy)-7-chloro-isoquinolin-1- ol hydrochloride (10). Rt = 1.08 min (Method B). Detected mass: 293.2/295.2 (M+H+).
frans-4-(lsoquinolin-6-yloxy)-cyclohexylamine (15)
6.1 g (53 mmol) of 4-amino-cyclohexanol were dissolved in 50 ml of dimethyl acetamide and 4.24 g (106 mmol) of sodium hydride (60%) were added at room temperature. After the reaction mixture was stirred for 30 minutes under argon, a solution of 6.49 g (35.3 mmol) of 6-fluoro-isoquinoline hydrochloride was added and the mixture was stirred at room temperature overnight. For workup, the solvent was removed in vacuo and the residue was dissolved in dichloromethane and washed twice with water. The organic layer was separated, dried with magnesium sulfate and evaporated to yield 8.64 g of the crude product, which was used without further purification. Rt = 0.77 min (Method B). Detected mass: 243.1 (M+H+).
frans-N-^lsoquinolin-β-yloxyJ-cyclohexyll-acetamide (16)
8.4 g (34.7 mmol) of 4-(isoquinolin-6-yloxy)-cyclohexylamine (15) were dissolved in 100 ml of dichloromethane/pyridine (4:1). At 0 0C a solution of 3.27 g (41.6 mmol) of acetyl chloride in 10 ml of dichloromethane was added and the reaction mixture was stirred at room temperature. After 2 h, the solution was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. After washing twice with 2 N HCI, the product was transferred to the aqueous phase. The HCI-layers were adjusted to alkaline pH by addition of solid NaOH and extracted three times with dichloromethane. Drying the organic layers with magnesium sulfate and evaporation of the solvent gave 7.69 g of the crude product. After silica gel chromatography 4.48 g of the title compound were isolated. Rt = 0.87 min (Method A). Detected mass: 285.2 (M+H+).
frans-N-[4-(2-Oxy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (17)
Starting from N-[4-(isoquinolin-6-yloxy)-cyclohexyl]-acetamide (16) the title compound was obtained following the method described for 7-chloro-6-fluoro-isoquinoline 2-oxide (5). Rt = 1.01 min (Method A). Detected mass: 301.2 (M+H+).
frans-N-[4-(1-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (18)
N-[4-(2-Oxy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (17) was converted to the title compound following the protocol described for 1 ,7-dichloro-6-fluoro-isoquinoline (6). The crude product was purified by preparative HPLC. Rt = 1.49 min (Method B). Detected mass: 319.1/321.1 (M+H+).
frans-N-[4-(1 -Benzyloxy-isoquinolin-β-yloxyJ-cyclohexylJ-acetamide (19)
975 mg (3.06 mmol) of N-[4-(1-chloro-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (18) were dissolved in 20 ml of dimethyl acetamide and 992 mg (9.17 mmol) of benzyl alcohol were added. After addition of 367 mg (9.17 mmol) of sodium hydride (60 %), the reaction mixture was stirred for 3 h at room temperature and for 1 h at 80 0C. Then, the solvent was removed in vacuo, the residue was dissolved in dichloromethane and washed three times with water. The organic layer was dried with magnesium sulfate and evaporated. Final purification by preparative HPLC yielded 680 mg of the title compound. R1 = 1.75 min (Method B). Detected mass: 391.2 (M+H+).
frans-6-(4-Amino-cyclohexyloxy)-2H-isoquinolin-1 -one (20)
680 mg (1.74 mmol) of N-[4-(1-benzyloxy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (19) were heated in 2 N HCI in an autoclave at 120 0C until complete conversion is achieved. The solvent is removed in vacuo and the residue is purified by preparative HPLC. The product fractions were evaporated and dissolved in 2 N HCI. After lyophilisation 182 mg of the title compound could be obtained as hydrochloride. Rt = 0.97 min (Method B). Detected mass: 259.2 (M+H+).
c/s-4-(lsoquinolin-6-yloxy)-cyclohexylamine (21 )
Starting from 6-fluoro-isoquinoline hydrochloride and c/s-4-amino-cyclohexanol the title compound was prepared following the protocol described for compound (15). Rt = 0.64 min (Method B). Detected mass: 243.2 (M+H+).
c/s-N-[4-(lsoquinolin-6-yloxy)-cyclohexyl]-acetamide (22)
Starting from c/s-4-(isoquinolin-6-yloxy)-cyclohexylamine (21) the title compound was prepared following the protocol described for the compound (16). Rt = 0.90 min (Method B). Detected mass: 285.1 (M+H+). c/s-N-[4-(2-Oxy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (23)
Starting from c/s-N-[4-(isoquinolin-6-yloxy)-cyclohexyl]-acetamide (22) the title compound was obtained following the method described for 7-chloro-6-fluoro- isoquinoline 2-oxide (5). Rt = 0.80 min (Method C). Detected mass: 301.2 (M+H+).
cis- 4-(2-Oxy-isoquinolin-6-yloxy)-cyclohexylamine (24)
2.43 g (8.1 mmol) of cis-N-[4-(2-oxy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (23) were refluxed in 50 ml of 2 N HCI for 16 h. Evaporation of the solvent gave 2.46 g of the title compound (crude product) as HCI-salt. Rt = 0.59 min (Method C). Detected mass: 517.3; 259.2; 130.2 [(2M+H+), (M+H+), 1/2(M+H+)].
c/s-4-(1-Chloro-isoquinolin-6-yloxy)-cyclohexylamine (25)
2.46 g of cis- 4-(2-oxy-isoquinolin-6-yloxy)-cyclohexylamine (24, crude product) were heated to 100 0C in 20 ml POCI3. After 1 h the mixture is cooled to room temperature and poured on ice. The aqueous solution is brought to an alkaline pH by addition ofsodium hydroxide and extracted three times with dichloromethane. The combined organic layers were dried with magnesium sulfate and the solvent was removed under reduced press ure to yield 1.14 g of the title compound as crude product, which was used without further purification. Rt = 0.90 min (Method C). Detected mass: 277.1/279.2 (M+H+). c/s-[4-(1-Chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butylester (26)
1.14 g of cis-4-(1-chloo-isoquinolin-6-yloxy)-cyclohexylamine (25, crude product) was dissolved in 20 ml of dichloromethane. At 0 0C a solution of 1.17 g (5.35 mmol) of di- tert-butyl dicarbonate in 5 ml of dichloromethane was added and the solution was stirred at room temperature. After 1 h, the solution was washed with water, dried and evaporated, to yield 1.65 g of the title compound, which was used without further purification. Rt = 1.77 min (Method C). Detected mass: 377.1/379.1 (M+H+).
c/s-[4-(1-Benzyloxy-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (27)
Starting from cis- [4-(1-chloro-isoquinolin-6-yloxy)-cyclohexyl]-carbamic acid tert-butyl ester (26, crude product) the title compound was prepared following the protocol described for frans-N-[4-(1-benzyloxy-isoquinolin-6-yloxy)-cyclohexyl]-acetamide (19). Final chromatography on a preparative HPLC gave a mixture of the desired product and the partially deprotected derivative having a free amino group. Rt = 2.01 min (Method C). Detected mass: 449.2 (M+H+).
c/s-6-(4-Amino-cyclohexy!oxy)-2H-isoquinolin-1 -one (28)
The title compound was prepared by stirring cis-[4-(1-Chloro-isoquinolin-6-yloxy)- cyclohexyl]-carbamic acid tert-butyl ester (27) at room temperature in methanol/2 N HCI (1 :1). After complete conversion, the solvent was removed under reduced pressure and the residue was purified by preparative HPLC. The obtained trifluoroacetate was converted to the corresponding hydrochloride by dissolving the compound in 2 N HCI and evaporation of the solvent. After dissolving the residue in water and lyophilisation, the desired product (HCI-salt) was isolated as a colourless solid. Rt = 0.75 min (Method B). Detected mass: 259,2 (M+H+).
General procedure A for the reductive amination reaction:
0.243 mmol of the amine building block (hydrochloride), 0.243 mmol of the aldehyde and 0.365 mmol of triethyl amine were stirred in 3 ml of HC(OMe)3 for 1 h at room temperature. The mixture is cooled to -10 °C, 1.75 ml of a freshly prepared DMF solution containing 1.215 mmol of NaHB(OAc)3 and 1.215 mmol of HOAc is added. Stirring is continued at -10 0C for 30 min, the mixture is then allowed to warm to room temperature and left at room temperature over night. 0.5 ml of water was added and the mixture was evaporated, dissolved in DMF and mono- and bis-akylated products, if obtained, were purified by preparative HPLC. The purified products were dissolved in 1 ml of HCI in isopropanol (5-6M) and left over night at RT (cleaves BOC/tBu ester groups off some of the products). 2 ml of water were added and the solution is freeze- dried to yield the hydrochlorides of the products.
According to this procedure the following products were obtained as hydrochlorides from the mentioned amine and carbonyl component (Table 1)
Table 1:
General procedure B for the reductive amination reaction:
150 mg (0.46 mmol) of 6-cis-(4-amino-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one hydrochloride (10) were dissolved in 10 ml of methanol. After addition of molecular sieves 4 A, 92.3 mg (0.57 mmol) of triethyl amine, 273.8 mg (4.56 mmol) of acetic acid and 0.57 mmol of the corresponding aldehyde, a solution of 86.0 mg (1.37 mmol) of sodium cyanoboro hydride is added dropwise and the mixture is stirred at room temperature until complete conversion is achieved. In some cases it was necessary to heat the mixture to 70 0C to achieve complete conversion. For the isolation of the products the solution was filtered and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane, washed with 1 N NaOH and sat. sodium chloride solution, dried with magnesium sulfate and evaporated. The mono- or bis alkylated products, if obtained, were purified by preparative HPLC or precipitated from methanolic HCI The obtained trifluoroacetates were stirred in 2 N HCI/Methanol, evaporated, dissolved in water and freeze dried to yield the desired products as hydrochlorides.
Boc-protected products were deprotected during the evaporation of the HPLC-product fractions, which contained 0.1% TFA, or during the subsequent stirring in 2 N HCI/Methanol.
According to this procedure the following products were obtained as hydrochlorides from amine (10) and the mentioned aldehyde (Table 2)
7-Bromo-6-fluoro-isoquinoline 2-oxide (93)
Starting from (92) the title compound was prepared following the method described for 7-chloro-6-fluoro-isoquinoline 2-oxide (5). Rt = 0.93 min (Method C). Detected mass: 242.2/244.2 (M+H+).
7-Bromo-1 -chloro-6-fIuoro-isoquinoline (94)
Starting from 7-bromo-6-fluoro-isoquinoline 2-oxide (93) the desired product was synthesized according to the protocol described for 1 ,7-dichloro-6-fluoro-isoquinoline (6). Rt = 1.70 min (Method C). Detected mass: 260.0/262.0 (M+H+).
7-Bromo-6-fIuoro-2H-isoquinolin-1 -one (95)
12.9 g (49.5 mmol) 7-bromo-1-chloro-6-fluoro-isoquinoline (94) were dissolved in 250 ml of acetic acid. After addition of 38.7 g (0.5 mol) of ammonium acetate, the solution is stirred at 100 0C. After 3 h, the solvent was removed under reduced pressure and the residue was poured into water. The precipitate is filtered and dried to yield 9.91 g (83%) of the title compound. Rt = 1.15 min (Method C). Detected mass: 242.2/244.1 (M+H+).
7-Bromo-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1 -one (96)
9.66 g (39.9 mmol) of 7-Bbromo-6-fluoro-2H-isoquinolin-1-one (95) were dissolved in 180 ml of dimethyl acetamide and 1.92 g (48.0 mmol) of sodium hydride (60%) were added. After 1 h at room temperature a solution of 7.50 g (48.0 mmol) of 4-methoxy benzylchloride in 25 ml of dimethyl acetamide was added. The mixture was stirred at room temperature until complete conversion was achieved. The solvent was removed under reduced pressure, the residue was taken up in saturated sodium bicarbonate solution and extracted three times with dichloromethane. The organic layers were dried with magnesium sulfate and evaporated to yield 16.8 g of a dark oil as crude product, which was stirred in methanol. Filtration of the precipitate gave 6.56 g of the title compound as a yellow solid. The mother liquor was evaporated and the residue purified by preparative HPLC to yield additional 2.62 g of the desired product. Rt = 1.71 min (Method C). Detected mass: 362.3/364.3 (M+H+).
β-c/s^-Amino-cyclohexyloxyJ-y-bromo^^-methoxy-benzylJ-ZH-isoquinolin-i- one (97)
135 mg (0.625 mmol) of c/s-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester were dissolved in 2.5 ml of dimethyl acetamide and 30 mg (0.75 mmol) of sodium hydride (60%) were added. After stirring for 15 minutes at room temperature 181 mg (0.5 mmol) of 7-bromo-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1 -one (96) were added and stirring was continued. To achieve complete conversion, additional 30 mg of sodium hydride (60%) were added after 3 h. After stirring overnight 2 ml of acetic acid followed by 2 ml of 2 N HCI were added and the mixture was stirred at 50 0C until the deprotection of the Boc-group was complete. The solvent was removed under reduced pressure, the residue dissolved in saturated sodium bicarbonate solution and extracted three times with dichloromethane. The organic layers were dried with magnesium sulfate and evaporated. Final purification by preparative HPLC gave 83 mg of the product as trifluoroacetate. R1 = 1.31 min (Method B). Detected mass: 457.2/459.2 (M+H+). 6-c/s-(4-Amino-cyclohexyloxy)-7-bromo-2H-isoquinolin-1-one (98)
62 mg (0.11 mmol) of 6-(4-amino-cyclohexyloxy)-7-bromo-2-(4-methoxy-benzyl)-2H- isoquinolin-1-one trifluoroacetate (97) were dissolved in 2 ml of TFA and heated in a microwave oven at 140 0C for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in 2 N HCI and washed twice with dichloromethane. The combined organic layers were extracted with 2 N HCI and the combined aqueous solutions were evaporated. The residues were dissolved in water and freeze dried. Final purification by preparative HPLC gave 8 mg of the desired product as trifluoroacetate. Rt = 0.86 min (Method B). Detected mass: 337.1/339.1 (M+H+).
β-frans^-Amino-cyclohexyloxyJ^-bromo-Σ^-methoxy-benzylJ-ΣH-iso-quinolin- 1-one (99)
Starting with frans-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester and 7-bromo- 6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (96) the title compound was synthesized following the protocol described for 6-c/s-(4-amino-cyclohexyloxy)-7- bromo-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (97). Rt = 1.34 min (Method B). Detected mass: 457.2/459.2 (M+H+).
6-frans-(4-Amino-cyclohexyloxy)-7-bromo-2H-isoquinolin-1-one (100)
Starting from 6-frans-(4-amino-cyclohexyloxy)-7-bromo-2-(4-methoxy-benzyl)-2H-iso- quinolin-1-one (99) the desired product was prepared by the methode described for 6- c/s-(4-amino-cyclohexyloxy)-7-bromo-2H-isoquinolin-1-one (98). The compound was isolated as trifluoroacetate. R1 = 0.88 min (Method B). Detected mass: 337.1/339.1 (M+H+).
7-Chloro-6-fluoro-2H-isoquinolin-1-one (101)
Starting from 1 ,7-dichloro-6-fluoro-isoquinoline (6) the title compound was prepared following the protocol described for 7-bromo-6-fluoro-2H-isoquinolin-1-one (95). R4 = 1.11 min (Method C). Detected mass: 198.2 (M+H+).
7-Chloro-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1 -one (102)
Starting from 7-chloro-6-fluoro-2H-isoquinolin-1-one (101) the title compound was prepared following the protocol described for 7-bromo-6-fluoro-2-(4-methoxy-benzyl)- 2H-isoquinolin-1-one (96). R1 = 1.66 min (Method C). Detected mass: 318.3 (M+H+).
1 -Benzyloxy-7-chloro-6-fluoro-isoquinoline (103)
14.74 g (74.6 mmol) of 7-chloro-6-fluoro-2H-isoquinolin-1-one (101) were dissolved in 150 ml of toluene. After addition of 30.86 g (111.9 mmol) of silver carbonate and 15.31 g (89.5 mmol) of benzyl bromide, the mixture was stirred at 80 0C for 3 h. After cooling down to room temperature, the reaction mixture was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane and washed with water, dried with magnesium sulfate and evaporated. Final purification by preparative HPLC gave 11.63 g of the title compound. Rt = 2.51 min (Method B). Detected mass: 288.1/290.1 (M+H+).
General Procedure for the reaction of the arylchlorides 7-chloro-6-fluoro-2-(4- methoxy-benzyl)-2H-isoquinolin-1-one (102) and 1-benzyloxy-7-chloro-6-fluoro- isoquinoline (103) with grignard reagents under Fe(acac)3 catalysis. 2 mmol of the respective arylchloride and 35.3 mg (0.1 mmol) of iron(lll) acetylacetonate were dissolved in 24 ml of THF and 2 ml of NMP were added. At 0 0C 2.4 mmol of the grignard reagent were added via syringe under argon and the reaction was stirred at 0 0C for 10 minutes. To achieve complete conversion, in some cases another 0.6 mmol of the grignard reagent were added and stirring was continued for 10 minutes.
In the case of the N-PMB-protected compounds, the reaction was quenched by pouring into 1M HCI. The O-Benzyl protected analogs were quenched by pouring into saturated NH4CI-solution. The mixture was evaporated and the residue was dissolved in dichloromethane and washed with water. The organic layer was dried with Na2SO4 and the solvent was removed under reduced pressure. Final purification by preparative HPLC gave the desired 7-alkylated derivatives.
According to this procedure the following products were obtained from the mentioned arylchloride and Grignard reagent (Table 3) 6-cis-(4-Amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-7-propyl-2H-isoquinolin-1- one (109)
58 mg (0.38 mmol) of cis 4-aminocyclohexanol hydrochloride were dissolved in 10 ml of dimethyl acetamide. Under argon, 38 mg (0.96 mmol) of sodium hydride (60%) were added and the reaction was stirred for 30 minutes at room temperature. After addition of a solution of 100 mg (0.31 mmol) of 6-fluoro-2-(4-methoxy-benzyl)-7-propyl-2H- isoquinolin-1-one (105) the solution was stirred at 80 0C. To obtain complete conversion, the same amounts of the 4-aminocyclhexanol hydrochloride and sodium hydride were added twice and the temperature was increased to 110 0C. After complete conversion, the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried with magnesium sulfate and evaporated. After purification by preparative HPLC the desired product was isolated as trifluoroacetate. Rt = 1.14 min (Method C). Detected mass: 421.6 (M+H+).
The following compounds were prepared as trifluoroacetates by the protocol described for 6-cis-(4-Amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-7-propyl-2H-isoquinolin-1-one (109) (Table 4):
Deprotection of the N-PMB-protected isoquinolinones 109, 110 and 111
The protected starting compounds were heated in TFA in a microwave oven at 140 0C until complete conversion was observed. Evaporation of the solvent and purification by preparative HPLC gave the desired deprotected products as trifluoroacetates, which were dissolved in 2 N HCI and evaporated. After dissolving the residue in water and lyophilization, the compounds were isolated as HCI-salts.
Deprotection of the O-benzyl protected Isoquinolinone 112
4-(1-Benzyloxy-7-cyclopropyl-isoquinolin-6-yloxy)-cyclohexylamine (112) was stirred in 2 N HCI at room temperature until conversion is complete. After evaporation of the solvent under reduced pressure, the crude product was purified by preparative HPLC, which gave the desired product as trifluoroacetate. The product was dissolved in 2 N
HCI and the solvent was removed under reduced pressure. After dissolving the residue in water and lyophilization, the product was isolated as HCI-salt.
After deprotection of the compounds 109 to 112, the following compounds were isolated as HCI salts (Table 5):
Table 5
General procedure C for the reductive amination reaction:
82 mg (0.25 mmol) of 6-frans-(4-amino-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one hydrochloride (14) were dissolved in 3 ml of trimethoxy methane. 0.25 mmol of the corresponding aldehyde or ketone were added (dissolved in 0.2 ml of THF or as a solid) followed by 48 mg (0.375 mmol) of triethylamine. After 1 h at room temperature the solution was cooled to -10 0C and a solution of 265 mg (1.25 mmol) of sodium triacetoxy borohydride in 1.5 ml DMF was added, followed by 73.5 mg (1.225 mmol) of acetic acid. After 30 min at 0 0C1 the solution was left at room temperature overnight. For workup, 0.5 ml of water were added and the solvent was removed under reduced pressure. The residue was purified by preparative HPLC. The obtained trifluoroacetates were dissolved in 1.0 ml of a 5-6 M HCI solution in isopropanol and left at room temperature overnight. After addition of 2.0 ml of water, the solutions were lyophilized yielding the desired products as HCI-salts.
The compounds listed in table 6 below were synthesized according to this method and obtained as HCI salt:
Table 6
6-[cis-4-(Cyclopropylmethyl-amino)-cyclohexyloxy]-2H-Jsoquinolin-1 -one (125)
125 was obtained as hydrochloride using the previously described general method employing cyclopropane carbaldehyde and cis-6-(4-amino-cyclohexyloxy)-2H- isoquinolin-1-one (28) as starting materials. Rt = 1.04 min (Method B). Detected mass: 313.2 (M+H+).
7-Benzylsulfanyl-6-fIuoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1 -one (126)
500 mg (1.38 mmol) of 7-bromo-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1 -one (96), 627.3 mg (1.52 mmol) of tributyltin benzylthiolate, 96.2 mg (1.66 mmol) of freshly dried potassium fluoride and 24.0 mg (0.041 mmol) of XANTPHOS were dissolved in 5 ml of NMP and stirred for 15 min at room temperature. After addition of 19.0 mg (0.021 mmol) of Pd2dba3, the reaction mixture was stirred at 100 0C. To achieve complete conversion, another 0.01 mmol of Pd2dba3 were added and stirring was continued at 100 0C. After 5 h the solution was cooled to room temperature, diluted with ethyl acetate (10 ml) and treated with 5% KF-solution. The mixture was stirred vigorously for 15 minutes and filtered. The filtrate was separated and the organic phase was washed twice with water and once with saturated sodium chloride solution. After drying with magnesium sulfate, the organic layer was evaporated and the crude product was purified by preparative HPLC. Rt = 1.83 min (Method C). Detected mass: 406.5 (M+H+). β^-Amino-c/s-cyclohexyloxyJ-y-benzylsulfanyl^^-methoxy-benzyO-ZH-iso- quinolin-1-one (127)
90 mg (0.59 mmol) of cis 4-amino-cyclohexanol hydrochloride were dissolved in 10 ml dimethyl acetamide and 59.3 mg (1.48 mmol) of sodium hydride (60%) were added. After stirring 30 minutes at room temperature, a solution of 200 mg (0.49 mmol) of 7- benzylsulfanyl-6-fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (126) in 20 ml of dimethyl acetamide was added and the mixture was stirred at 80 0C for 1 h, then at 130 0C for 3 h. Another 1.2 equivalents of cis 4-amino-cyclohexanol hydrochloride and 2.5 equivalents of sodium hydride were added and the temperature was increased to 160 0C. After 8h the solution is cooled down to room temperature and the solvent is removed under reduced pressure. The residue is dissolved in dichloromethane, washed with water and dried with magnesium sulfate. After evaporation of the solvent and purification by preparative HPLC, the title compound was isolated as trifluoroacetate. R1 = 1.18 min (Method C). Detected mass: 501.6 (M+H+).
N-{4-[7-Benzylsulfanyl-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro-isoquinolin-6- yloxy]-c/s-cyclohexyl}-acetamide (128)
45 mg (0.073 mmol) of 6-(4-amino-c/s-cyclohexyloxy)-7-benzylsulfanyl-2-(4-methoxy- benzyl)-2H-iso-quinolin-1-one (127) were dissolved in 5 ml of dichloromethane and 14.8 mg (0.146 mmol) of triethylamine were added. At 0 0C, 6.9 mg (0.088 mmol) of acetylchloride were added and the solution was stirred at room temperature. After 2h, dichloromethane was added and the solution was washed with 2 N HCI and saturated sodium bicarbonate solution. After drying with magnesium sulfate and evaporation of the solvent, the title compound was isolated as crude product, which was used without further purification. Rt = 1.53 min (Method C). Detected mass: 543.6 (M+H+).
6-(4-Acetylamino-c/s-cyclohexyloxy)-4-chloro-2-(4-methoxy-benzyl)-1-oxo-1,2- dihydro-isoquinoline-7-sulfonyl chloride (129)
37 mg of N-{4-[7-benzylsulfanyl-2-(4-methoxy-benzyl)-1-oxo-1 ,2-dihydro-isoquinolin-6- yloxy]-cyclohexyl}-acetamide (128, crude product) were dissolved in 5 ml of dichloromethane. At 0 0C, 16.4 mg (0.273 mmol) of acetic acid, 4.9 mg (0.273 mmol) of water and 273 μl (0.273 mmol) of sulfuryl chloride (1 M in dichloromethane) were added. After 30 minutes, ethyl acetate was added and the solution was washed with sodium bicarbonate solution (2%), water and saturated sodium chloride solution. The organic layer was dried with Na2SO4 and evaporated. The so obtained crude product was used without further purification. Rt = 1.55 min (Method C). Detected mass: 553.5 (M+H+).
N-{4-[4-Chloro-2-(4-methoxy-benzyl)-1-oxo-7-sulfamoyl-1,2-dihydro-isoquinolin- 6-yloxy]-c/s-cyclohexyl>-acetamide (130)
To a solution of 29 mg of 6-(4-acetylamino-c/s-cyclohexyloxy)-4-chloro-2-(4-methoxy- benzyl)-1 -oxo-1 ,2-dihydro-isoquinoline-7-sulfonyl chloride (129, crude product) in 2 ml of THF 2 ml of 33% aqueous ammonia solution were added. After 1h at room temperature the solvent was removed under reduced pressure and the crude product was used without further purification. Rt = 1.22 min (Method C). Detected mass: 534.5 (M+H+).
6-(4-Amino-c/s-cyclohexyloxy)-4-chloro-2-(4-methoxy-benzyl)-1-oxo-1,2-dihydro- isoquinoline-7-sulfonic acid amide (131)
32 mg of N-{4-[4-chloro-2-(4-methoxy-benzyl)-1-oxo-7-sulfamoyl-1 ,2-dihydro- isoquinolin-6-yloxy]-c/s-cyclohexyl}-acetamide (130, crude product) were dissolved in 5 ml of ethanol and 15 ml of 2 N HCI and heated for 2 h at 90 0C. The solvent was removed under reduced pressure and the residue was dissolved in 6 N HCI and heating at 90 0C was continued for 2Oh. After cooling down to room temperature, the aqueous solution was evaporated and the title compound was isolated as HCI-salt (crude product). Rt = 1.00 min (Method C). Detected mass: 492.5 (M+H+).
6-(4-Amino-cιs-cyclohexyloxy)-4-chloro-1-oxo-1,2-dihydro-isoquinoline-7- sulfonic acid amide (132)
Crude131 was dissolved in 15 ml of trifluoroacetic acid and heated for 3 h at 140 0C under microwave conditions. After evaporation of the solvent, the crude product was purified by preparative HPLC, which delivers the title compound as trifluoroacetate. R1 = 0.90 min (Method B). Detected mass: 372.3 (M+H+). 1 -Benzyloxy-7-chloro-6-(1 ,4-dioxa-spiro[4.5]dec-8-yloxy)-isoquinoline (133)
1.26 g ( 8.34 mmol) of dioxa-spiro[4.5]decan-8-ol were dissolved in 50 ml of dimethyl acetamide and 695.2 mg (17.4 mmol) of sodium hydride (60%) were added. After stirring 30 minutes at room temperature a solution of 2.0 g (6.95 mmol) of 1-benzyloxy- 7-chloro-6-fluoro-isoquinoline (103) in 50 ml of dimethyl acetamide was added and stirring was continued at room temperature. After 1 h the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane and washed with water. The organic layer was dried with magnesium sulfate and evaporated, which gave 3.30 g of the crude product, which was used without further purification. Rt = 2.05 min (Method C). Detected mass: 426.5 (M+H+).
7-Chloro-6-(4-oxo-cyclohexyloxy)-2H-isoquinolin-1-one (134)
3.30 g of 1-benzyloxy-7-chloro-6-(1,4-dioxa-spiro[4.5]dec-8-yloxy)-isoquinoline (133, crude product) were stirred in 30 ml of 6 N HCI/acetone (1:2) at room temperature. After 3 h the reaction mixture was poured on saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried with magnesium sulfate and evaporated. The crude product was purified by preparative HPLC. Rt = 1.34 min (Method B). Detected mass: 292.0 (M+H+).
Starting from 7-chloro-6-(4-oxo-cyclohexyloxy)-2H-isoquinolin-1-one (134), the following compounds were synthesized as hydrochlorides in analogy to the general procedure B for the reductive amination reactions (Table 7): Table 7
6-(trans-4-Amino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1 -one (137)
a) 6-Fluoro-7-methyl-2H-isoquinolin-1 -one
To a solution of 10.0 g (55.5 mmol) of 3-fluoro-4-methyl-cinnamic acid in 80 ml of acetone were subsequently added at 0 0C 6.74 g (66.6 mmol) of triethylamine in 10 ml of acetone followed by 7.83 g (72.2 mmol) of ethyl chloroformate. After stirring for 2 h at 0 to 5 0C a solution of 4.0 g (61.1 mmol) of sodium azide in 9.5 ml of water was added. After stirring for 1 additional h the reaction mixture was poured onto 200 ml of ice water and extraced twice with chloroform. The organic phase was dried over magnesium sulfate, 40 ml diphenylether were added and the chloroform was cautiously removed in vacuo. The residue was then added dropwise into 50 ml of diphenylether, which had been preheated to 2450C. After complete addition it was stirred further for 1 h at 230 - 250 0C. After cooling down to 1500C the reaction mixture was poured into 270 ml of heptane and after further cooling in an ice bath the precipitated product was filtered by suction and 4.1 g 6-fluoro-7-methyl-2H-isoquinolin- 1-one were obtained.
b) 6-Fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one
To a solution of 9.17 g (51.8 mmol) of 6-fluoro-7-methyl-2H-isoquinolin-1-one in 80 ml of DMF were added 20.2 g (62.1 mmol) of cesium carbonate and then 8.92 g (56.9 mmol) of 4-methoxybenzylchloride. After stirring at room temperature for 90 minutes the reaction mixture was poured into 600 ml of water, stirred for 1 h, and then the precipitated product was isolated by suction. From the mother liquor additional producted was isolated by chromatography with heptane / ethyl acetate (80:20). The combined products were recrystallized from ethyl acetate and 8.39 g 6-fIuoro-2-(4- methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one were received. c) 6-(trans-4-Amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1- one
To a solution of 1.48 g (9.75 mmol) of trans-4-aminocyclohexanol hydrochloride in 20 ml of dimethylacetamide where added 1.95 g (48.77 mmol) of sodium hydride (60 %) and the mixture was stirred for 15 minutes. Subsequently 2.90 g (9.75 mmol) of 6- fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one in 30 ml of dimethylacetamide were added and the reaction mixture was heated to 800C for 2 days. After cooling the mixture was poured into 300 ml of ice water and the precipitated crude product was purified by chromatography. First the remaining starting material was eluted whith ethyl acetate / heptane (2:1) und finally the desired product was eluted by pure methanol giving 1.98 g 6-(trans-4-amino-cyclohexyloxy)-2-(4- methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one.
d) 6-(trans-4-Amino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one hydrochloride
2.64 g (6.7 mmol) of 6-(trans-4-amino-cyclohexyloxy)-2-(4-methoxy-benzyl)-7-methyl- 2H-isoquinolin-1-one and 15.3 g (134.5 mmol) of trifluoroacetic acid were heated for 2 h in an microwave oven at 1500C. Then the excess trifluoroacetic acid was distilled off in vacuo and the residue was diluted with 130 ml of 1 M hydrochlorid acid. The aqueous phase was washed with methylene chloride 3 times and then it was freeze dried to give a hydrochloride, which was recrystallized from isopropanol. This furnished 1.1 g 6-(trans-4-amino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one (137) as hydrochloride. Rt = 0.92 min (Method B). Detected mass: 273.22 (M+H+).
β^cis^-Amino-cyclohexyloxyJ-y-methyl^H-isoquinolin-i -one (138)
a) cis-4-Aminocyclohexanol hydrochloride To a solution of 30.0 g (0.265 mol) of cyclohexanone oxime in 300 ml of methylene chloride and 38 ml of ethanol was slowly added at 0 0C 34.5 g (0.318 mol) of tert- butyl-hypochlorite. The resulting dark blue solution was cooled to -2O0C and then 31.9 g (0.398 mol) of 1 ,3-cyclohexadiene were added and the mixture was stored in a freezer at 5°C for 2 days until the blue color had disappeared. The reaction mixture was concentrated to 50% of its volume and then 600 ml of diethyl ether were slowly added. After stirring overnight the resulting precipitate was isolated by suction to yield 29,0 g of 2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene hydrochloride. 5.0 g (0.045 mol) of this material were hydrogenated with 3.0 g (0.013 mol) platinum oxide at 2 bar hydrogen pressure. After 7 h the catalyst was filtered off and a solution of 20 ml 4 M hydrochloric acid in dioxane was added. After evaporation the residue was recrystallized from 30 ml isopropanol giving 3.1 g of cis-4-aminocyclohexanol hydrochloride.
b) 6-(cis-4-Aminocyclohexyloxy)-7-methyl-2H-isoquinolin-1 -one hydrochloride
From 2.55 g (16.8 mmol) of cis-4-aminocyclohexanol hydrochloride and 5.0 g (16.8 mmol) of 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one (137, step b) were prepared 0.98 g of 6-(cis-4-amino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one hydrochloride as described in example 137 steps c and d. Rt = 0.99 min (Method B). Detected mass: 273.18 (M+H+).
6-(cis-4-Ethylamino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1 -one (139)
0.2 g (0.65 mmol) of δ-fcis^ amino-cyclohexyloxy^-methyl^H-isoquinolin-i-one hydrochloride (138), 69 mg (0.68 mmol) of triethylamine and 35 mg (0.78 mmol) of acetaldehyde were stirred in 13 ml of dry methanol for 4 h at 5°C. After addition of 37 mg (0.97 mol) of sodium borohydride the mixture was stirred overnight at room temperature. Since incomplete conversion of the starting amine was observed the same amounts of actetaldehyde and sodium borohydride were added again sequentially within 2 h. After further stirring for 2 hours the reaction mixture was acidified with concentrated hydrochloric acid and the methanol was evaporated. The aqueous residue was washed with ethyl acetate and then saturated with potassium carbonate and extracted whith methylene chloride to give 145 mg of 6-(cis-4- ethylamino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one (139). Rt = 0.89 min (Method A). Detected mass: 301.20 (M+H+).
6-(cis-4-lsobutylamino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one (140)
From 0.2 (0.65 mmol) of 6-(cis-4-amino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one hydrochloride (138) and isobutyraldehyde were obtained analogous to example 139 151 mg of δ-^-isobutylamino-cyclohexyloxyJ-T-methyl^H-isoquinolin-i-one. Rt = 1.10 min (Method A). Detected mass: 329.20 (M+H+).
Analogous to examples 139 and 140 the following compounds were prepared from the respective amines and aldehyde (Table 8).
Table 8
^cis^-DJethylamino-cyclohexyloxyJ-y-methyl^H-isoquinolin-i -one (146)
A reaction mixture consisting of 150 mg (0.49 mmol) 6-(cis-4-amino-cyclohexyloxy)-7- methyl-2H-isoquinolin-1-one hydrochloride (example 138), 38 mg (0.63 mmol) of acetic acid, 43 mg (0.97 mmol) of acetaldehyde, molecular sieves and 515 mg (2.4 mmol) of sodium triacetoxy borohydride in 5 ml of methylene chloride was stirred overnight. The reaction mixture was added to 10 ml of 1 M sodium hydroxide solution and extracted twice with a mixture of methylene chloride and isopropanol. After drying and evaporation 122 mg of 6-(cis-4-diethylamino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1- one (146) were obtained. Rt = 0.99 min (Method B). Detected mass: 329.17 (MH-H+).
6-(cis-4-lsopropylamino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one (147)
Analogous to example 146 121 mg of 6-(cis-4-isopropylamino-cyclohexyloxy)-7- methyl-2H-isoquinolin-1-one (147) were obtained from 150 mg (0.49 mmol) of 6-(cis-4- amino-cyclohexyloxy)-7-methyl-2H-isoquinolin-1-one hydrochloride (138) by reaction with acetone. Rt = 1.07 min (Method B). Detected mass: 315.13 (M+H+).
2,2,2-Trif luoro-N-(trans-4-hydroxy-cyclohexyl)-acetamide (148)
25 g of trans-4-aminocyclohexanol hydrochloride were suspended in 250 mL of dry dioxane and 30 mL of sodium methylate solution (30% in methanol, 1 equivalent) were added. 39.3 mL of ethyl trifluoroacetate were added and the reaction mixture was allowed to stir until the reaction was complete. The reaction mixture was evaporated, taken up in 50 ml_ of 0.1 N HCI and extracted several times with dichloromethane:isopropanol 3:1. The combined organic layer was extracted once with 0.1 N HCI and brine, dried over sodium sulfate and evaporated to dryness to yield 29.0 g of 148. Rt = 0.69 min (Method C). Detected mass: 212.2 (M+H+).
2,2,2-Trifluoro-N-(4-hydroxy-cyclohexyl)-N-methyl-acetamide (149)
5 g of 2,2,2-trifluoro-N-(4-hydroxy-cyclohexyl)-acetamide (148) were dissolved in 25 mL of dimethyl acetamide, 625 mg of 95% sodium hydride were added and the reaction mixture was cooled to 00C. 1.64 mL of iodomethane were added slowly and the reaction mixture was allowed to warm to room temperature. Upon completion, the reaction mixture was poured into water, extracted three times with methyl tert. butyl ether and the combined organic layer was extracted once with brine, dried over sodium sulfate and evaporated to dryness. The residue was taken up in water and lyophilized to remove remainders of dimethyl acetamide to yield 4.0 g of product. Rt = 0.95 min (Method C). Detected mass: 226.2 (M+H+).
trans-4-Methylamino-cyclohexanol (150)
2g of 2,2,2-thfluoro-N-(4-hydroxy-cyclohexyl)-N-methyl-acetamide (149) were suspended in 10 mL of 1 N HCI and heated in a microwave at 150° until conversion was complete. The resulting solution was lyophilized and the residue was taken up in water and lyophilized again, twice to yield 1.45 g of 4-methylamino-cyclohexanol (150). Rt = 0.13 min (Method C). Detected mass: 130.3 (M+H+).
2-(trans-4-Methoxy-benzyl)-6-(4-methylamino-cyclohexyloxy)-2H-isoquinolin-1- one (151)
630 mg of sodium hydride (95%) were suspended in 40 mL of dimethyl acetamide. 1.45 g of 4-methylamino-cyclohexanol (150), dissolved in 40 mL of dimethyl acetamide, were added dropwise and 15 min. later 2.48 g of 6-fluoro-2-(4-methoxy- benzyl)-2H-isoquinolin-1-one (177), dissolved in another 40 mL of dimethyl acetamide, were added. The reaction mixture was stirred at 80 0C until the reaction was complete. The mixture was poured into an ice-water mixture, extracted three times with methyl- tert.-butyl ether and the combined organic layer was dried over sodium sulfate and evaporated. Water was added and the crude product was subjected to lyophilization to remove remainders of dimethyl acetamide.
The obtained product is sufficiently pure for further conversion. Rt = 1.24 min (Method B), detected mass: 393.2 (M+H+).
6-(trans-4-Methylamino-cyclohexyloxy)-2H-isoquinolin-1 -one (152)
2.46 g of 2-(4-methoxy-benzyl)-6-(4-methylamino-cyclohexyloxy)-2H-isoquinolin-1-one (151) were dissolved in 15 mL of TFA and heated in a microwave oven at 150 0C for 2 h. Methanol was added and the reaction mixture was evaporated. The solution was taken up in 1 N HCI and extracted three times with dichloromethane. The combined dichloromethane layers were extracted with 1 N HCI twice and the combined HCI layers were lyophilized, the residue was taken up in water and lyophilized again to yield 1.31 g of 6-(4-methylamino-cyclohexyloxy)-2H-isoquinolin-1-one (152) as hydrochloride. Rt = 0.81 min (Method B). Detected mass: 273.2 (M+H+).
The following two products were obtained as hydrochlorides by the same reaction sequence described for the synthesis of 152, using appropriate alkyl halides for the alkylation of 148.
6-(trans-4-EthyIamino-cyclohexyloxy)-2H-isoquinolin-1 -one (153)
Rt = 0.85 min (Method B). Detected mass: 287.1 (M+H+).
6-(trans-4-lsopropylamino-cyclohexyloxy)-2H-isoquinolin-1 -one (154)
Rt = 1.16 min (Method B). Detected mass: 315.2 (M+H+).
General procedure D for the reductive amination reaction:
250 mg of 153 (or of another monosubstituted isoquinolonone-amine) are dissolved in 8 mL of dichloromethane and 6 mL of DMF. 3 eq. of aldehyde, 1.3 eq. of acetic acid, 300 mg of molecular sieves and 3 eq. of sodium triacetoxy borohydride are added. The reaction mixture is stirred for 16 h at 55 0C. The mixture is poured into 5 mL of 1 N NaOH and 25 mL of dichloromethane and 10 mL of isopropanol are added. The organic layer is separated and the aqueous layer is extracted three times with isopropanokdichloromethane 1 :3. The combined organic layer is evaporated to dryness and the residue is purified by HPLC and eventually converted into the corresponding HCI salts by addition of 2N HCI and subsequent lyophilization.
The following compounds were prepared according to this procedure and obtained as free base or hydrochlorides (Table 9)
6-Fluoro-isoquinolinone (176)
4.8 mL (90.3 mmol, 1.5 eq.) of thionyl chloride was added portionwise to a solution of 10 g (60.2 mmol) of 3-fluoro cinnamic acid in 44 ml of chloroform and 1 ml of DMF. The reaction was heated to reflux for 2.5 h. Then the solvents were distilled to to yield 11.4 g of the raw acid chloride, which was used without any further purifcation.
The acid chloride was dissolved in 45 mL of acetone. At 0 0C 8.03 g of NaN3 (123.5 mmol, 2 eq.) were added portionwise. Then 41 mL of water were added while the temperature was kept below 5 0C. The reaction was stirred for another 1.5 h. Then 55 ml of chloroform were added. The mixture was extracted with 80 mL of water followed by 40 mL of brine. After drying over Na2SO4 and filtration 14 mL of diphenyl ether were added and most of the chloroform was removed in vacuo (without heating). A total removal of the chloroform should be avoided.
The solution containing the azide, diphenyl ether and the remaining chloroform was added dropwise at 260 0C within 15 minutes to a solution of 10 mL of tributyl amine in 97 ml of diphenyl ether. A vigorous reaction can be observed during the addition. The reaction was stirred for another 20 minutes at 260 0C. After cooling to room temperature 270 mL of n-heptane were added. The precipitated product was filtered off and washed with ether to yield 5.65 g of the title compound. MS (DCI) Detected mass: 164.0 (M+H+).
6-Fluoro-2-(4-methoxy-benzyl)-2H-isoquinolin-1-one (177)
169 μL of p-methoxybenzylchloride (1.24 mmol, 1.1 eq) were added to a suspension of 200 mg of 6-fluoro-isoquinolinone (176) (1.13 mmol) and 368 mg of Cs2CO3 (1.36 mmol, 1.2 eq) in 3 mL of DMF. The mixture was stirred for 2 h and then poured on ice. The precipitate was filtered, washed with water and dried to yield 300 mg of the title compound. LCMS Method B, retention time 1.76 min, detected mass 284.14 [M+H]+
4-Ethyl-6,7-difluoro-2H-isoquinolin-1-one (178)
4-Ethyl-6,7-difluoro-2H-isoquinolin-1-one (178) was obtained by the same method described for the synthesis of 176, using (3,4-difluoro-phenyl)-pent-2- enoic acid as a starting material. Rt = 1.46 min (Method B). Detected mass: 210.1 (M+H+). The used acrylic acid was synthesized from the corresponding aldehyde in similar fashion as described in the literature (see for instance: J. Med. Chem. 2005, 48, 71-90).
6-(trans-4-Amino-cyclohexyloxy)-4-ethy l-7-f!uoro-2H-isoquinolin-1 -one (179)
6-(4-Amino-cyclohexyloxy)-4-ethyl-7-fluoro-2H-isoquinolin-1-one (179) was synthesized as hydrochloride by a similar reaction sequence as described for the conversion 137 (steps b, c and d), using 178 as the starting material. Rt = 0.97 min (Method B). Detected mass: 305.2 (M+H+). LC/MS-Methods:
Method A:
Stationary phase: CoI YMC Jsphere 33 x 2 Gradient: ACN+0,05% TFA : H2O + 0.05% TFA 5:95(0 min) to 95:5(3.4 min) to 95:5(4.4 min)
Flow 1 ml_/min
Method B: Stationary phase: CoI YMC Jsphere 33 x 2 Gradient: ACN+0,05% TFA : H2O + 0.05% TFA 5:95(0 min) to 95:5(2.5 min) to 95:5(3.0 min)
Flow 1 mL/min
Method C:
Stationary phase: CoI YMC Jsphere ODS H80 20 x 2 Gradient: ACN : H2O + 0.05% TFA
4:96(0 min) to 95:5(2.0 min) to 95:5(2.4 min)
Flow 1 mL/min
Method D:
Stationary phase: CoI YMC Jsphere 33 x 2.1 Gradient: Grad ACN+0.08% FA:H2O+0.1%FA (Formic Acid)
5:95 (Omin) to 95:5 (2.5min) to 95:5 (3min) Flow 1.3 mL/min
Determination of Rho kinase inhibition
To measure Rho-kinase inhibition, IC50 values were determined according to the following protocol: Buffer: 25mM Tris pH7.5; 0.02% BSA; 5% Glycerol; 0.008% Triton X100; 2% DMSO, 1mM DTT; 1mM MgCI2; 0.5μCi/well γ33P ATP Enzyme: ROCKII or ROKα) (Upstate, Catalog # 14-451) 0.1 ng/μl Final concentration of ATP in reaction mixture 40μM Biotinylated substrate, diluted to 0.25μM with buffer described above (without ATP)
1. 10μl Tris buffer (± Inhibitor)
2. Add 30 μl_ of enzyme solution
3. Start the reaction with 30μL of mix substrate/ATP/ATP33 4. Incubate for 20 min at room temperature
5. Stop reaction with 30μL of 50 mM EDTA
6. Transfer 50 μl_ of stopped solution to Streptavidin Flash Plate plus, Perkin Elmer,
SMP 103A
7. Incubate for 30 min at RT 8. Wash 4 times with 300 μl of PBS/0.1 % Tween 20 9. Radioactivity in the well was determined
The following products/compounds were tested in said assay by using the respective form (salt or free base) obtained as in the examples described above and the following activities were measured.
The given activity is denoted as the negative decadal logarithm of the IC50 (PIC50) as follows:
+: plC50 <3.0 ++: 3.0<plC50<4.0 +++ 4.0<plC50<5.0 ++++: 5.0<plC50 <6.0 6.0 < PlC50

Claims

Claims
1. A compound of the formula (I)
or of the formula (I1)
wherein
R1 is H, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, [(C-| -C6)alkylene]o-1 -(C3-C8)cycloalkyl, [(C-| -C6)alkylene]o_i -(C5-C1 n)heterocyclyl,
[(C1 -C6)alkylene]θ-1 -(C6-C1 o)aryl,
C(O)-(C1-C6)alkyl, C(O)(C2-C6)alkenyl, C(O)-(C2-C6)alkynyl,
C(O)-I(C1 -C6)alkylene]θ-1 -(C3-C8)cycloalkyl,
C(O)-I(C1 -C6)alkylene]o-1-(C5-C10)heterocyclyl, or C(OH(Ci -C6)alkylene]θ-1-(C6-Cio)aryl,
R2 is H, (C1-C6)alkyl, [(C1-C6)alkylenelo.-i-R1,
[(C1 -C6)alkylene]o-1 -O-(Ci-C6)alkyl, [(C1 -C6)alkylene]o-1 -O-R', [(C1 -C6)alkylene]0- 1-NH2, [(C1-C6)alkylene]o.i-NH(C1-C6)alkylI [(C1-C6)alkylene]o-i-N[(C1-C6)alkyl]2, [(C1-C6)alkylene]0.1-CH[R']2, [(C1-C6)alkylenelo-i-C(O)-R1, [(C1 -C6)alkylene]θ-1 -C(O)NH2,
[(C1 -C6)alkylene]rj-1 -C(O)NH-R', or [(C1-C6)alkylene]o-1-C(O)N[R']2 ;
R3 is H, halogen, CN, (C-i-CβJalkyl, (C-i-CβJalkylene-R1, OH, O-R", NH2, NHR", NR"R" or NH-C(O)-R",
R4 is H, halogen, hydroxy, CN, (Ci-C-6)alkyl, (C3-C8)cycloalkyl, (C<|-C6)alkylene-R';
R5 is H, halogen, CN, NO2, (C-i-C^alkyl, (C2-C6)alkenyl, R', (C1-C6)alkylene-(C6-Cio)aryl, (C2-C6)alkenylene-(C6-Cio)aryl,
(C1-C6)alkylene-(C5-Cio)heterocyclyl, NH2, NH-R1, NH-SO2H, NH-SO2-(Ci -C6)alkyl, NH-SO2-R', NH-C(O)-(C1 -C6)alkyl, NH-C(O)-R', C(O)N[(C1-C6)alkyl]2, C(O)OH or C(O)O-(C1-C6)alkyl;
RQ and RQ are independently of each other H, R', (C-|-C8)alkyl, (C1-C6)alkylene-R1, (C1-C6)alkylene-O-(C-|-C6)alkyl, (C1-C6)alkylene-O-R1, (C-|-C6)alkylene-CH[R']2, (Ci- C6)alkylene-C(O)-R', (C1-C6)alkylene-C(O)NH2, (Ci-C6)alkylene-C(O)NH-R', or (C-|-C6)alkylene-C(O)N[R']2;
R7 and Re are independently of each other H, halogen, CN, NO2, (C-|-C6)alkyl, O-(C1-C6)alkyl, O-[(C-|-C6)alkylene]o-1-R', (C2-C6)alkenyl, R', (C2-C6)alkenylene- (C6-Cio)aryl, (C-|-C6)alkylene-R', NH2, NH-R', NH-SO2H, NH-SO2-(Ci -CβJalkyl, NH- SO2-R', SO2-NH2, SO2-NHR', NH-C(O)-(Ci-C6)alkyl, NH-C(O)-R', C(0)N[(C<|- C6)alkyl]2, C(O)OH or C(O)O-(C1 -C6)alkyl;
Rg is halogen or (C1-C6)alkyl;
n is O, 1 , 2, 3 or 4; and L is O or O-(C1-C6)alkylene;
wherein R' is (Cβ-Cgjcycloalkyl, (C5-C1 o)heterocyclyl or (C6-C1 rj)aryl; and
R" is (C3-C8)cycloalkyl, (C5-C10)heterocyclyl, (C6-C10)aryl, (C1-C6)alkyl,
(C-i-CβJalkylene-R1, (C1-C6)alkylene-O-tC-i-C6)alkyl, (C1-C6)alkylene-O-R'l Or (C1- C6)alkylene-NRxRy; and
wherein Rx and Ry are independently of each other (C-|-C6)alkyl, (C5-C10)heterocyclyl, (C6-C-ioJaryl, (C1-C4)alkylene-(C5-C10)heterocyclyl, (C1-C4)alkylene-(C6-C10)aryl, (C-i-C6)alkylene-NH^-i-C6)alkyl, (C-i-C6)alkylene-N[(C1-C6)alkyl^, (C-i-C6)alkylene-NKCδ-C10)ary^, or (C1-C4)alkylene-N[(C5-C10)heterocyclyl]2; and
wherein in residues R4, R5, R7 and R8 one alkyl or alkylene hydrogen atom can optionally be substituted by OH, OCH3, COOH, COOCH3, NH2, NHCH3, N(CH3)2, CONH2, CONHCH3 or CON(CH3)2 or an alkyl or alkylene may be halogenated once or more;
or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.
2. A compound of the formula (I) according to claim 1 characterized by a compound of the formula (II)
3. A compound of the formula (I1) according to claim 1 characterized by a compound of the formula (H')
4. A compound according to any of claims 1 to 3, wherein RQ and RQ' are independently of each other H, (C-|-C6)alkyl, R', (C-|-C4)alkylene-(C3-C8)cycloalkyl, (C<|-C4)alkylene-(C5-C<ιo)heterocyclyl, (C-|-C4)alkylene-C(O)-(C5-C-| o)heterocyclyl, (C 1 -C4)alkylene-C(O)-(C6-C 1 rj)aryl or (C i -C6)alkylene-(C6-C 1 Q)aτy\.
5. A compound according to any of claims 1 to 4, wherein Rg and RQ' are independently of each other H1 (C-|-C6)alkyl, (C5-C<ιo)heterocyclyl, (C3-C8)cycloalkyl, (C-|-C4)alkylene-(C3-C8)cycloalkyl, (C-|-C4)alkylene-(C5-C-|o)heterocyclyl or (C1-C6)alkylene-(C6-C10)aryl.
6. A compound according to any of claims 1 to 5, wherein Re is H, (C-|-C6)alkyl, (C3-C6)cycloalkyl or (Ci-C4)alkylene-(C3-C6)cycloalkyl, and RQ' is H, (C1-C6)alkyl, (C3-C8)cycloalkyl, (Ci-C4)alkylene-(C3-C8)cycloalkyl, (C5-Cio)heterocyclyl, (C-|-C4)alkylene-(C5-C-|o)neterocyclyl or
7. A compound according to any of claims 1 to 6, wherein RQ is H, (C-|-C6)alkyl and RQ' is H1 (C«|-C6)alkyl, (C3-C8)cycloalkyl, (C<|-C4)alkylene-(C3-C8)cycloalkyl, (C5-C<ιo)heterocyclyl, (Ci-C4)alkylene-(C5-C-|o)neterocyclyl or (C-|-C6)alkylene-(C6- Cio)aryl.
8. A compound according to any of claims 1 to 7, R6 is H, (C-|-C6)alkyl and R6' is H, (C-|-C6)alkyl, (C3-C8)cycloalkyl, (C-|-C4)alkylene-(C3-C8)cycloalkyl, (C-|-C4)alkylene-(C5-C-|o)heterocyclyl in which heterocyclyl is unsubstituted or substituted by (C^-C^alkyl or halogen, or is (C1-C6)alkylene^C6-C-iøJaryl in which aryl is unsubstituted or substituted by halogen, (C-|-C4)alkyl, O-(C-|-C4)alkyl or SO2- (Ci-C4)alkyl.
9. A compound according to any of claims 1 to 8, wherein RQ is H, (C-|-C6)alkyl and RQ' is H, (C«|-C6)alkyl, (C3-C8)cycloalkyl.
10. A compound according to any of claims 1 to 9, wherein RQ is H and RQ' is H1
(C-|-C6)alkyl, (C3-C8)cycloalkyl.
11. A compound according to any of claims 1 to 10, wherein RQ and RQ' are H.
12. A compound according to any of claims 1 to 11 , wherein R5 is H, halogen, CN,
(C-|-C6)alkyl, R', NH-(C6-C10)aryl or (C-|-C6)alkylene-R\
13. A compound according to any of claims 1 to 12, wherein R5 is H, halogen, (C1-C6)alkyl, R', NH-(C6-C10)aryl or (C1-C6)alkylene-R1.
14. A compound according to any of claims 1 to 13, wherein R5 is H, halogen, (C-i-C^alkyl, (C6-C1 o)aryl, (Cs-C10)heteroaryl, NH-(C6-C10)aryl or (C-i-C^alkylene^C6-C-ioJaryl.
15. A compound according to any of claims 1 to 14, wherein R5 is H, halogen,
(C-|-C6)alkyl, phenyl or (C5-C6)heteroaryl.
16. A compound according to any of claims 1 to 15, wherein R5 is H, halogen or (Ci-C6)alkyl.
17. A compound according to any of claims 1 to 16, wherein R5 is H or halogen.
18. A compound according to any of claims 1 to 17, wherein R5 is H.
19. A compound according to any of claims 1 to 18, wherein R4 is H, halogen, CN, (C1-C6)alkyl, NH-(C6-C<ιo)aryl or (C1-C6)alkylene-R'.
20. A compound according to any of claims 1 to 19, wherein R4 is H, halogen,
(C-i-CβJalkyl, NH-(C6-C10)aryl or (Ci-CβJalkylene-R1.
21. A compound according to any of claims 1 to 20, wherein R4 is H, halogen, (C<|-C6)alkyl, N H-(Cg-C <io)ary' or (C-|-C2)alkylene-(C6-C<ιo)aryl.
22. A compound according to any of claims 1 to 21 , wherein R4 is H, halogen, or (C1-C6)alkyl.
23. A compound according to any of claims 1 to 22, wherein R4 is H or (C^CeOalkyl.
24. A compound according to any of claims 1 to 20, wherein R4 is H.
25. A compound according to any of claims 1 to 24, wherein R7 and Re are independently of each other H, halogen, CN, (C-|-C6)alkyl, O-(C-|-C6)alkyl, (C2- C6)alkenyl, R' or (C<|-C6)alkylene-(C3-C8)cycloalkyl.
26. A compound according to any of claims 1 to 25, wherein R7 and Re are independently of each other H, halogen, CN, (C-|-C4)alkyl, O-(Ci-C4)alkyl, (C2-C4)alkenyl, phenyl, (C5-C6)heteroaryl, (C3-Cβ)cycloalkyl or (C<|-C4)alkylene- (C3-C6)cycloalkyl.
27. A compound according to any of claims 1 to 26, wherein R7 and Rs are independently of each other H, halogen, (C-|-C4)alkyl, O-(Ci-C4)alkyl or (C3-C6)cycloalkyl.
28. A compound according to any of claims 1 to 27, wherein R7 is H, halogen, (C-|-C4)alkyl or (C3-C6)cycloalkyl and Rs is H.
29. A compound according to any of claims 1 to 28, wherein R7 and RQ are H.
30. A compound according to any of claims 1 to 29, wherein Rg is halogen or (C-] - C4)alkyl.
31. A compound according to any of claims 1 to 30, wherein Rg is Cl, F, methyl or ethyl.
32. A compound according to any of claims 1 to 31 , wherein n is 0, 1 , 2 or 3.
33. A compound according to any of claims 1 to 32, wherein n is 0 or 1.
34. A compound according to any of claims 1 to 29, wherein n is 0.
35. A compound according to any of claims 1 to 34, wherein R3 is H, halogen, (C<|- C6)alkyl, (C-|-C4)alkylene-R\ O-R" or NHR".
36. A compound according to any of claims 1 to 35, wherein R3 is H, (C-|-C6)alkyl or NHR".
37. A compound according to any of claims 1 to 36, wherein R3 is H, (C-|-C4)alkyl, NH-(C5-C6)heterocyclyl or NH-phenyl.
38. A compound according to any of claims 1 to 37, wherein R3 is H, (C-|-C4)alkyl, NH-(C5-C6)heteroaryl containing one or more N atoms or NH-phenyl.
39. A compound according to any of claims 1 to 38, wherein R3 is H.
40. A compound according to any of claims 1 to 39, wherein L is attached to the 4- position of the cyclohexyl ring
L is attached to the 3-position of the cyclohexyl ring
41. A compound according to any of claims 1 to 40, wherein L is attached to the 4- position of the cyclohexyl ring.
42. A compound according to any of claims 1 to 41 , wherein L is O-methylene, O-ethylene or O.
43. A compound according to any of claims 1 to 42, wherein L is O-methylene, O-ethylene or O attached to the 4-position of the cyclohexyl ring.
44. A compound according to any of claims 1 to 43, wherein L is O.
45. A compound according to any of claims 1 to 3, wherein
R3 is H, halogen, CN, (C-|-C6)alkyl, (Ci-CβJalkylene-R1, OH, O-R", NH2, or NHR";
R4 is H, halogen, hydroxy, CN, (C-|-C6)alkyl, (C3-C8)cycloalkyl, (C<|-C6)alkylene-R';
R5 is H, halogen, CN, NO2, (C<\-CQ)a\ky\, (C2-C6)alkenyl, R', (C1-C6)alkylene-(C6-Cio)aryl, (C2-C6)alkenylene-(C6-Cio)aryl, (C1-C6)alkylene-(C5-C-|o)heterocyclyl, NH2, NH-R', NH-SO2H, NH-SO^C-i-C6)alkyl, NH-SO2-R1, NH-C(O)-(Ci-C6)alkyl, NH-C(O)-R', C(O)N[(C1-C6)alkyl]2, C(O)OH or C(O)O-(C1-C6)alkyl;
RQ and RQ' are independently of each other H, (C3-C8)cycloalkyl, (C-i-CβJalkyl, (C1-C6)alkylene-R', (C<|-C6)alkylene-O-(C1-C6)alkyl, (C-|-C6)alkylene-O-R', (C1-C6)alkylene-CHtR1^, (C1-C6)alkylene-C(O)NH2, (C1-C6)alkylene-C(O)NH-R', or (C1-C6)alkylene-C(O)N[R']2;
R7 and Rg are independently of each other H, halogen, CN, NO2, (Ci-Cβ)alkyl, (C2-C6)alkenyl, R', (C2-C6)alkenylene-(C6-Cio)aryl, (C1-C6)alkylene-R1, NH2, NH-R', NH-SO2-(C1 -C6)alkyl, NH-SO2-R', SO2-NH2, SO2-NHR', NH-C(O)-(Ci -C6)alkyl, NH" C(O)-R', C(O)N[(Ci-Cβ)alkyl]2. C(O)OH or C(O)O-(C1 -C6)alkyl;
Rg is halogen or (Ci -C6)alkyl; n is 0, 1 , 2; and
L is O or O-(C-|-C3)alkylene;
or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.
46. A compound according to any of claims 1 to 3, wherein
R3 is H, halogen, CN, (C-|-C6)alkyl, (C<|-C2)alkylene-R' or NHR";
R4 is H1 halogen, CN, (C-|-C6)alkyl, (C3-C8)cycloalkyl, (Ci-C2)alkylene-R';
R5 is H, halogen, CN, NO2, (C-i-CβJalkyl, (C2-C6)alkenyl, R1, (C1-C6)alkylene-(C6-C<io)aryl, (C2-C6)alkenylene-(C6-Cirj)aryl,
(C-|-C6)alkylene-(C5-Cio)heterocyclyl, NH2, NH-R', NH-C(O)-(Ci -CβJalkyl, or
C(O)NKCi-C6)alkyl^;
R6 and Rø' are independently of each other H, (C3-C8)cycloalkyl, (Ci-Cgjalkyl, or
(Ci-C3)alkylene-R';
R7 and Rg are independently of each other H, halogen, CN, NO2, (C-|-C6)alkyl,
(C2-C6)alkenyl, R', (C2-C3)alkenylene-(C6-C10)aryl, (C-i-CaJalkylene-R1, NH-R', NH- SO2-(C1 -C6)alkyl, or SO2-NH2;
Rg is halogen or (C1-C6)alkyl;
n is 0 or 1 ; and
L is O or O-methylene; or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.
47. A compound according to any of claims 1 to 3, wherein
R3 is H, halogen, CN, (C<|-C6)alkyl, (C<|-C2)alkylene-R' or NHR";
R4 is H, halogen, CN, (C-|-C4)alkyl, (C3-C6)cycloalkyl, (Ci-C2)alkylene-R';
R5 is H, halogen, CN, NO2, (C-|-C6)alkyl, (C^-C^alkenyl, R', (C1-C6)alkylene-(C6-C10)aryl, (C2-C6)alkenylene-(C6-Cio)aryl, (C 1 -C6)alkylene-(C5-C 1 n)heterocyclyl, N H-R1 ;
Rβ is H, (C3-C6)cycloalkyl or (C 1 -Chalky I;
RQ is H, (C3-C8)cycloalkyl, (C<|-C8)alkyl, or (C-|-C3)alkylene-R';
R7 and Rs are independently of each other H, halogen, CN, NO2, (C1-C6)alkyl, (C2-C6)alkenyl, R', (C2-C3)alkenylene-(C6-Cio)aryl. (C<|-C3)alkylene-R\ NH-SO2-(C1-C6)alkyl, or SO2-NH2;
Rg is halogen or (C-|-C4)alkyl; n is 0 ; and L is O;
or their pharmaceutically acceptable salts and/or stereoisomeric forms and/or physiologically functional derivatives.
48. A compound of the formulae (I) or (I1) and/or their physiologically acceptable salts and/or stereoisomeric forms according to any of claims 1 to 47 for use as a medicament.
49. Use of at least one compound of the formula (I) or (I1) and/or their physiologically acceptable salts and/or stereoisomeric forms according to any of claims 1 to 47 for producing a medicament.
50. Use of a compound of the formulae (I) or (I1) and/or their physiologically acceptable salts and/or stereoisomeric forms according to any of claims 1 to 47 for the production of pharmaceuticals for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase.
51. Use of at least one compound of the formulae (I) or (I1) and/or their physiologically acceptable salts and/or stereoisomeric forms thereof according to any of claims 1 to 47 for producing a medicament for the treatment and/or prevention of hypertension, pulmonary hypertension, ocular hypertension, retinopathy, glaucoma, peripheral circulatory disorder, peripheral occlusive arterial disease (PAOD), coronary heart disease, angina pectoris, heart hypertrophy, heart failure, ischemic diseases, ischemic organ failure (end organ damage), fibroid lung, fibroid liver, liver failure, nephropathy, renal failure, fibroid kidney, renal glomerulosclerosis, organ hypertrophy, asthma, chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome, thrombotic disorders, stroke, cerebral vasospasm, cerebral ischemia, pain, neuronal degeneration, spinal cord injury, Alzheimer's disease, premature birth, erectile dysfunction, endocrine dysfunctions, arteriosclerosis, prostatic hypertrophy, diabetes and complications of diabetes, metabolic syndrome, blood vessel restenosis, atherosclerosis, inflammation, autoimmune diseases, AIDS, osteopathy, infection of digestive tracts with bacteria, sepsis or cancer development and progression.
52. A medicament comprising an effective amount of at least one compound of the formulae (I) or (I') and/or their physiologically acceptable salts and/or stereoisomeric forms thereof according to any of claims 1 to 47, physiologically tolerated excipients and carriers and, where appropriate, further additives and/or other active ingredients.
EP06776307A 2005-07-26 2006-07-20 Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors Active EP1912949B1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
PL06776307T PL1912949T3 (en) 2005-07-26 2006-07-20 Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors
SI200631175T SI1912949T1 (en) 2005-07-26 2006-07-20 Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors
EP06776307A EP1912949B1 (en) 2005-07-26 2006-07-20 Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors
CY20111101153T CY1112085T1 (en) 2005-07-26 2011-11-24 Cyclohexylamine isokinolone derivatives as RHO-kinase inhibitors

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP05016153 2005-07-26
PCT/EP2006/007140 WO2007012422A1 (en) 2005-07-26 2006-07-20 Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors
EP06776307A EP1912949B1 (en) 2005-07-26 2006-07-20 Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors

Publications (2)

Publication Number Publication Date
EP1912949A1 true EP1912949A1 (en) 2008-04-23
EP1912949B1 EP1912949B1 (en) 2011-08-24

Family

ID=35115842

Family Applications (1)

Application Number Title Priority Date Filing Date
EP06776307A Active EP1912949B1 (en) 2005-07-26 2006-07-20 Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors

Country Status (37)

Country Link
US (2) US8609691B2 (en)
EP (1) EP1912949B1 (en)
JP (1) JP5049970B2 (en)
KR (1) KR101336678B1 (en)
CN (1) CN101228132B (en)
AR (1) AR057082A1 (en)
AT (1) ATE521595T1 (en)
AU (1) AU2006274246B2 (en)
BR (1) BRPI0614063A2 (en)
CA (1) CA2615663C (en)
CR (1) CR9604A (en)
CY (1) CY1112085T1 (en)
DK (1) DK1912949T3 (en)
DO (1) DOP2006000177A (en)
EC (1) ECSP088136A (en)
ES (1) ES2372067T3 (en)
GT (1) GT200600327A (en)
HK (1) HK1123036A1 (en)
HN (1) HN2008000130A (en)
HR (1) HRP20110839T1 (en)
IL (1) IL188949A (en)
MA (1) MA29639B1 (en)
MX (1) MX2008000956A (en)
MY (1) MY146644A (en)
NI (1) NI200800024A (en)
NO (1) NO20080965L (en)
NZ (1) NZ565669A (en)
PE (1) PE20070181A1 (en)
PL (1) PL1912949T3 (en)
PT (1) PT1912949E (en)
RS (1) RS52241B (en)
RU (1) RU2440988C2 (en)
SI (1) SI1912949T1 (en)
TN (1) TNSN08038A1 (en)
TW (1) TWI412521B (en)
WO (1) WO2007012422A1 (en)
ZA (1) ZA200710952B (en)

Families Citing this family (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2006264043B2 (en) 2005-06-28 2012-04-26 Sanofi-Aventis Isoquinoline derivatives as inhibitors of Rho-kinase
CN101228132B (en) 2005-07-26 2012-10-10 塞诺菲-安万特股份有限公司 Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors
UA93882C2 (en) 2005-07-26 2011-03-25 Санофи-Авентис Piperidinyl-substituted isoquinolone derivatives as rho-kinase inhibitors
US7893088B2 (en) * 2006-08-18 2011-02-22 N.V. Organon 6-substituted isoquinoline derivatives
JP5271909B2 (en) * 2006-09-11 2013-08-21 エム・エス・ディー・オス・ベー・フェー 2- (1-oxo-1H-isoquinolin-2-yl) acetamide derivatives
BRPI0720862A2 (en) 2006-12-27 2014-02-25 Sanofi Aventis ISOKINOLINE AND ISOQUINOLINONE DERIVATIVES REPLACED AS RHO-KINASE INHIBITORS
WO2008077555A2 (en) 2006-12-27 2008-07-03 Sanofi-Aventis Substituted isoquinolines and their use as rho-kinase inhibitors
CN101611012B (en) * 2006-12-27 2012-11-14 塞诺菲-安万特股份有限公司 Cycloalkylamine substituted isoquinoline derivatives
KR101494452B1 (en) 2006-12-27 2015-02-16 사노피 Cycloalkylamine substituted isoquinoline and isoquinolinone derivatives
MY155009A (en) 2006-12-27 2015-08-28 Sanofi Aventis Cycloalkylamine substituted isoquinolone derivatives
KR20090094338A (en) 2006-12-27 2009-09-04 사노피-아벤티스 Substituted isoquinoline and isoquinolinone derivatives
CL2008000973A1 (en) 2007-04-05 2009-01-02 Astrazeneca Ab Compounds derived from 1-oxo-isoquinoline; preparation procedure; pharmaceutical composition; and its use in the treatment of chronic obstructive pulmonary diseases (COPD) and asthma.
JP5524071B2 (en) * 2007-10-24 2014-06-18 メルク・シャープ・アンド・ドーム・コーポレーション Heterocyclic phenylamide T-type calcium channel antagonist
RU2532481C2 (en) 2008-06-24 2014-11-10 Санофи-Авентис Bi- and polycyclic substituted isoquinoline and isoquinolinone derivatives, useful as rho-kinase inhibitors
PL2313374T3 (en) * 2008-06-24 2014-03-31 Sanofi Sa 6-substituted isoquinolines and isoquinolinones
KR101638326B1 (en) * 2008-06-24 2016-07-12 사노피 Substituted isoquinolines and isoquinolinones as Rho kinase inhibitors
BRPI0917936A2 (en) * 2008-08-25 2017-07-11 Irm Llc HEDGEHOG TRACK MODULATORS
AR073711A1 (en) 2008-10-01 2010-11-24 Astrazeneca Ab ISOQUINOLINE DERIVATIVES
TW201443023A (en) * 2013-01-18 2014-11-16 必治妥美雅史谷比公司 Phthalazinones and isoquinolinones as ROCK inhibitors
FI3640241T3 (en) 2013-10-18 2023-01-13 Bromodomain inhibitors
CA2927830A1 (en) * 2013-10-23 2015-04-30 Chugai Seiyaku Kabushiki Kaisha Quinazolinone and isoquinolinone derivative
FR3017868A1 (en) 2014-02-21 2015-08-28 Servier Lab ISOQUINOLINE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME
CN105085478B (en) * 2014-04-28 2019-04-12 南京明德新药研发股份有限公司 Isoquinolin sulphone amide derivative and its pharmaceutical composition and pharmaceutical applications
AR104259A1 (en) 2015-04-15 2017-07-05 Celgene Quanticel Res Inc BROMODOMINUM INHIBITORS
WO2016180918A1 (en) 2015-05-12 2016-11-17 Platod Combination of pharmacological and microfluidic features for improved platelets production
WO2017003723A1 (en) 2015-07-01 2017-01-05 Crinetics Pharmaceuticals, Inc. Somatostatin modulators and uses thereof
AU2017252276A1 (en) 2016-04-18 2018-11-15 Celgene Quanticel Research, Inc. Therapeutic compounds
US10150754B2 (en) 2016-04-19 2018-12-11 Celgene Quanticel Research, Inc. Histone demethylase inhibitors
WO2019023278A1 (en) 2017-07-25 2019-01-31 Crinetics Pharmaceuticals, Inc. Somatostatin modulators and uses thereof
WO2019236879A1 (en) * 2018-06-07 2019-12-12 Disarm Therapeutics, Inc. Inhibitors of sarm1
CN114874236B (en) * 2022-06-24 2023-05-05 中国工程物理研究院化工材料研究所 Five-membered aza condensed ring skeleton and preparation method thereof

Family Cites Families (52)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2485537B2 (en) 1977-04-13 1986-05-16 Anvar DIPYRIDO (4,3-B) (3,4-F) INDOLES, PROCESS FOR OBTAINING IT, THERAPEUTIC APPLICATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO1992002476A1 (en) 1990-07-31 1992-02-20 E.I. Du Pont De Nemours And Company Catalytic equilibration of selected halocarbons
US5480883A (en) * 1991-05-10 1996-01-02 Rhone-Poulenc Rorer Pharmaceuticals Inc. Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase
GB9516709D0 (en) 1995-08-15 1995-10-18 Zeneca Ltd Medicament
ZA9610741B (en) 1995-12-22 1997-06-24 Warner Lambert Co 4-Substituted piperidine analogs and their use as subtype selective nmda receptor antagonists
DE69737631T3 (en) 1996-08-12 2011-08-18 Mitsubishi Tanabe Pharma Corp. MEDICAMENTS CONTAINING Rho-KINASE INHIBITORS
JPH1087629A (en) 1996-09-18 1998-04-07 Fujisawa Pharmaceut Co Ltd New isoquinoline derivative, and its medicinal use
AU8872198A (en) 1997-08-29 1999-03-22 Zeneca Limited Aminometyl oxooxazolidinyl benzene derivatives
TW575567B (en) 1998-10-23 2004-02-11 Akzo Nobel Nv Serine protease inhibitor
US6541456B1 (en) 1999-12-01 2003-04-01 Isis Pharmaceuticals, Inc. Antimicrobial 2-deoxystreptamine compounds
US6784192B2 (en) 2000-01-20 2004-08-31 Eisai Co., Ltd. Piperidine compound and pharmaceutical composition thereof
US7217722B2 (en) * 2000-02-01 2007-05-15 Kirin Beer Kabushiki Kaisha Nitrogen-containing compounds having kinase inhibitory activity and drugs containing the same
AU2001239947A1 (en) 2000-02-29 2001-09-12 Curis, Inc. Methods and compositions for regulating adipocytes
GB0004887D0 (en) 2000-03-01 2000-04-19 Astrazeneca Uk Ltd Chemical compounds
AR033517A1 (en) 2000-04-08 2003-12-26 Astrazeneca Ab PIPERIDINE DERIVATIVES, PROCESS FOR THE PREPARATION AND USE OF THESE DERIVATIVES IN THE MANUFACTURE OF MEDICINES
GB0013060D0 (en) 2000-05-31 2000-07-19 Astrazeneca Ab Chemical compounds
AU2001296008A1 (en) 2000-10-27 2002-05-06 Takeda Chemical Industries Ltd. Process for preparing substituted aromatic compounds and intermediates therefor
WO2002055496A1 (en) 2001-01-15 2002-07-18 Glaxo Group Limited Aryl piperidine and piperazine derivatives as inducers of ldl-receptor expression
SE0101038D0 (en) 2001-03-23 2001-03-23 Astrazeneca Ab Novel compounds
WO2002088101A2 (en) 2001-04-27 2002-11-07 Vertex Pharmaceuticals Incorporated Inhibitors of bace
US7199147B2 (en) * 2001-06-12 2007-04-03 Dainippon Sumitomo Pharma Co., Ltd. Rho kinase inhibitors
GB0117899D0 (en) 2001-07-23 2001-09-12 Astrazeneca Ab Chemical compounds
WO2003024450A1 (en) 2001-09-20 2003-03-27 Eisai Co., Ltd. Methods for treating prion diseases
SE0104340D0 (en) 2001-12-20 2001-12-20 Astrazeneca Ab New compounds
KR20050019918A (en) * 2002-07-22 2005-03-03 아사히 가세이 파마 가부시키가이샤 5-Substituted Isoquinoline Derivatives
WO2004009555A1 (en) * 2002-07-22 2004-01-29 Asahi Kasei Pharma Corporation 5-substituted isoquinoline derivative
WO2004024717A1 (en) 2002-09-12 2004-03-25 Kirin Beer Kabushiki Kaisha Isoquinoline derivatives having kinasae inhibitory activity and drugs containing the same
ATE421324T1 (en) * 2003-03-11 2009-02-15 Novartis Ag USE OF ISOQUINOLINE DERIVATIVES TO TREAT CANCER AND DISEASES RELATED TO MAP KINASE
US20040225116A1 (en) 2003-05-08 2004-11-11 Payne Mark S. Nucleic acid fragments encoding nitrile hydratase and amidase enzymes from comamonas testosteroni 5-MGAM-4D and recombinant organisms expressing those enzymes useful for the production of amides and acids
US20040266755A1 (en) 2003-05-29 2004-12-30 Schering Aktiengesellschaft Prodrugs of 1-(1-hydroxy-5-isoquinolinesulfonyl) homopiperazine
EP1638939A2 (en) 2003-06-24 2006-03-29 Neurosearch A/S Aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
US7826566B2 (en) 2003-08-22 2010-11-02 4Links Limited Communication system
WO2005030791A2 (en) 2003-09-23 2005-04-07 Merck & Co., Inc. Isoquinolinone potassium channel inhibitors
JP4794446B2 (en) 2003-09-23 2011-10-19 メルク・シャープ・エンド・ドーム・コーポレイション Isoquinoline potassium channel inhibitor
US20050067037A1 (en) 2003-09-30 2005-03-31 Conocophillips Company Collapse resistant composite riser
JPWO2005035516A1 (en) * 2003-10-10 2006-12-21 小野薬品工業株式会社 Novel fused heterocyclic compounds and uses thereof
EP1689719A1 (en) 2003-11-25 2006-08-16 Eli Lilly And Company 7-phenyl-isoquinoline-5-sulfonylamino derivatives as inhibitors of akt (proteinkinase b)
WO2005074535A2 (en) 2004-01-30 2005-08-18 Eisai Co., Ltd. Cholinesterase inhibitors for spinal cord disorders
US20080312189A1 (en) 2004-03-05 2008-12-18 Eisai Co., Ltd. Cadasil Treatment with Cholinesterase Inhibitors
SE0400850D0 (en) 2004-03-30 2004-03-31 Astrazeneca Ab Novel Compounds
JP4969049B2 (en) * 2004-04-06 2012-07-04 株式会社アマダ Bending machine
US7517991B2 (en) * 2004-10-12 2009-04-14 Bristol-Myers Squibb Company N-sulfonylpiperidine cannabinoid receptor 1 antagonists
EP1741525A1 (en) 2005-07-06 2007-01-10 Trumpf Werkzeugmaschinen GmbH + Co. KG Device for supporting plate materials
UA93882C2 (en) 2005-07-26 2011-03-25 Санофи-Авентис Piperidinyl-substituted isoquinolone derivatives as rho-kinase inhibitors
CN101228132B (en) 2005-07-26 2012-10-10 塞诺菲-安万特股份有限公司 Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors
TW200745101A (en) 2005-09-30 2007-12-16 Organon Nv 9-Azabicyclo[3.3.1]nonane derivatives
JP4033221B2 (en) 2005-12-02 2008-01-16 ダイキン工業株式会社 Refrigerant heating device
US7618985B2 (en) 2005-12-08 2009-11-17 N.V. Organon Isoquinoline derivatives
TW200738682A (en) 2005-12-08 2007-10-16 Organon Nv Isoquinoline derivatives
US7893088B2 (en) 2006-08-18 2011-02-22 N.V. Organon 6-substituted isoquinoline derivatives
KR101494452B1 (en) 2006-12-27 2015-02-16 사노피 Cycloalkylamine substituted isoquinoline and isoquinolinone derivatives
WO2008077555A2 (en) 2006-12-27 2008-07-03 Sanofi-Aventis Substituted isoquinolines and their use as rho-kinase inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007012422A1 *

Also Published As

Publication number Publication date
ECSP088136A (en) 2008-02-20
MX2008000956A (en) 2008-03-27
ZA200710952B (en) 2008-11-26
KR101336678B1 (en) 2013-12-04
DK1912949T3 (en) 2011-11-28
HN2008000130A (en) 2010-12-27
RU2008106926A (en) 2009-09-10
NZ565669A (en) 2010-05-28
CY1112085T1 (en) 2015-11-04
JP2009502830A (en) 2009-01-29
ES2372067T3 (en) 2012-01-13
IL188949A0 (en) 2008-04-13
MA29639B1 (en) 2008-07-01
CR9604A (en) 2008-04-10
JP5049970B2 (en) 2012-10-17
AU2006274246B2 (en) 2012-07-12
TW200800906A (en) 2008-01-01
ATE521595T1 (en) 2011-09-15
HRP20110839T1 (en) 2011-12-31
US20110251226A1 (en) 2011-10-13
IL188949A (en) 2013-11-28
TNSN08038A1 (en) 2009-07-14
RU2440988C2 (en) 2012-01-27
CA2615663A1 (en) 2007-02-01
KR20080028970A (en) 2008-04-02
WO2007012422A1 (en) 2007-02-01
AR057082A1 (en) 2007-11-14
PE20070181A1 (en) 2007-03-07
TWI412521B (en) 2013-10-21
BRPI0614063A2 (en) 2011-03-09
DOP2006000177A (en) 2007-06-15
HK1123036A1 (en) 2009-06-05
SI1912949T1 (en) 2011-12-30
NO20080965L (en) 2008-02-22
CA2615663C (en) 2013-10-15
AU2006274246A1 (en) 2007-02-01
US8796458B2 (en) 2014-08-05
US8609691B2 (en) 2013-12-17
CN101228132B (en) 2012-10-10
GT200600327A (en) 2007-02-05
EP1912949B1 (en) 2011-08-24
MY146644A (en) 2012-09-14
NI200800024A (en) 2009-03-03
RS52241B (en) 2012-10-31
PL1912949T3 (en) 2012-01-31
US20080242699A1 (en) 2008-10-02
CN101228132A (en) 2008-07-23
PT1912949E (en) 2011-11-23

Similar Documents

Publication Publication Date Title
EP1912949B1 (en) Cyclohexylamin isoquinolone derivatives as rho-kinase inhibitors
EP2385047B1 (en) Piperidinyl-substituted isoquinolone derivatives
EP2102187B1 (en) Substituted isoquinoline and isoquinolinone derivatives as inhibitors of rho-kinase
AU2007338407B2 (en) Cycloalkylamine substituted isoquinolone derivatives
EP2125744B1 (en) Cycloalkylamine substituted isoquinolone and isoquinolinone derivatives
EP2125746B1 (en) Cycloalkylamine substituted isoquinoline derivatives
WO2008077556A1 (en) Cycloalkylamine substituted isoquinoline and isoquinolinone derivatives
EP2114920A1 (en) Substituted isoquinoline and isoquinolinone derivatives

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20080226

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

17Q First examination report despatched

Effective date: 20080527

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SANOFI

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602006024039

Country of ref document: DE

Effective date: 20111020

REG Reference to a national code

Ref country code: HR

Ref legal event code: TUEP

Ref document number: P20110839

Country of ref document: HR

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20111107

REG Reference to a national code

Ref country code: RO

Ref legal event code: EPE

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: HR

Ref legal event code: T1PR

Ref document number: P20110839

Country of ref document: HR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2372067

Country of ref document: ES

Kind code of ref document: T3

Effective date: 20120113

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

REG Reference to a national code

Ref country code: EE

Ref legal event code: FG4A

Ref document number: E006104

Country of ref document: EE

Effective date: 20111107

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20110402691

Country of ref document: GR

Effective date: 20120117

REG Reference to a national code

Ref country code: CH

Ref legal event code: PFA

Owner name: SANOFI

Free format text: SANOFI#174, AVENUE DE FRANCE#75013 PARIS (FR) -TRANSFER TO- SANOFI#54, RUE DE LA BOETIE#75008 PARIS (FR)

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: SANOFI

RAP2 Party data changed (patent owner data changed or rights of a patent transferred)

Owner name: SANOFI

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 11104

Country of ref document: SK

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E012768

Country of ref document: HU

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20120525

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602006024039

Country of ref document: DE

Effective date: 20120525

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20110839

Country of ref document: HR

Payment date: 20150609

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MC

Payment date: 20150609

Year of fee payment: 10

Ref country code: SK

Payment date: 20150615

Year of fee payment: 10

Ref country code: RO

Payment date: 20150608

Year of fee payment: 10

Ref country code: EE

Payment date: 20150610

Year of fee payment: 10

Ref country code: LT

Payment date: 20150611

Year of fee payment: 10

Ref country code: BG

Payment date: 20150609

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 20150729

Year of fee payment: 10

Ref country code: IS

Payment date: 20150609

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: PT

Payment date: 20150717

Year of fee payment: 10

Ref country code: FI

Payment date: 20150709

Year of fee payment: 10

Ref country code: IE

Payment date: 20150709

Year of fee payment: 10

Ref country code: CZ

Payment date: 20150703

Year of fee payment: 10

Ref country code: DK

Payment date: 20150713

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: HU

Payment date: 20150703

Year of fee payment: 10

Ref country code: SE

Payment date: 20150713

Year of fee payment: 10

Ref country code: LV

Payment date: 20150619

Year of fee payment: 10

Ref country code: AT

Payment date: 20150625

Year of fee payment: 10

Ref country code: SI

Payment date: 20150615

Year of fee payment: 10

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20150624

Year of fee payment: 10

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 11

REG Reference to a national code

Ref country code: HR

Ref legal event code: PBON

Ref document number: P20110839

Country of ref document: HR

Effective date: 20160720

REG Reference to a national code

Ref country code: EE

Ref legal event code: MM4A

Ref document number: E006104

Country of ref document: EE

Effective date: 20160731

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

Effective date: 20170131

REG Reference to a national code

Ref country code: LT

Ref legal event code: MM4D

Effective date: 20160720

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 521595

Country of ref document: AT

Kind code of ref document: T

Effective date: 20160720

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160801

REG Reference to a national code

Ref country code: SK

Ref legal event code: MM4A

Ref document number: E 11104

Country of ref document: SK

Effective date: 20160720

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160721

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160720

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160731

Ref country code: RO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160720

Ref country code: LT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160720

Ref country code: LV

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160720

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160721

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160720

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160720

Ref country code: BG

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170228

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160720

Ref country code: SK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160720

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20170201

Ref country code: SI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160721

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20170120

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 12

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20170405

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160720

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GR

Payment date: 20170613

Year of fee payment: 12

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160720

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 20170613

Year of fee payment: 12

Ref country code: PL

Payment date: 20170613

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 20170712

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20170724

Year of fee payment: 12

Ref country code: ES

Payment date: 20170801

Year of fee payment: 12

Ref country code: IT

Payment date: 20170720

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: TR

Payment date: 20170704

Year of fee payment: 12

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20160731

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 13

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: NL

Ref legal event code: MM

Effective date: 20180801

REG Reference to a national code

Ref country code: BE

Ref legal event code: MM

Effective date: 20180731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180731

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180801

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20190207

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180720

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20190619

Year of fee payment: 14

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20190917

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180721

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 20190710

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20190717

Year of fee payment: 14

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180720

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602006024039

Country of ref document: DE

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20200720

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200720

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20200731

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20210202

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20180720